Pyrano- and thiopyranoindole derivatives, compositions and methods of use

ABSTRACT

Pyranoindole and thiopyranoindole derivatives characterized by having an amino(lower)alkyl radical attached to either or both the 1 and 9 position of a pyrano[3,4-b]indole or thiopyrano[3,4-b]indole nucleus or having said radical attached to the 1 position of a pyrano[4,3-b]indole or thiopyrano[4,3-b]indole nucleus are disclosed. The amino portion of the amino(lower)alkyl radical may be further substituted with one or two lower alkyl groups or incorporated into a heterocyclic amine radical. The derivatives having the amino(lower)alkyl radical only at position 1 are further substituted at position 1 and may be optionally substituted at positions 3,4,5,6,7,8, and 9. The pyrano[3,4-b]indole or thiopyrano[3,4-b]indole derivatives having the amino(lower)alkyl radical only at position 9 possess two substituents at position 1 and may be optionally substituted at position 3,4,5,6,7, and 8; the derivatives having an amino(lower)alkyl radical at both positions 1 and 9 are further substituted at position 1 and may be optionally substituted at positions 3,4,5,6,7 and 8. The pyrano-and thiopyranoindole derivatives of this invention are useful antidepressant and antiulcer agents. Methods for the preparation and use of these derivatives are also disclosed.

This Application is a Continuation-in-Part of each of our earlier filed Applications, U.S. Pat. application Ser. No. 377,837, filed July 9, 1973, now U.S. Pat. No. 3,880,853, issued Apr. 29, 1975 and U.S. Pat. application Ser. No. 217,627, filed Jan. 13, 1972 (now U.S. Pat. No. 3,852,285, issued Dec. 3, 1974).

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to novel pyranoindole and thiopyranoindole derivatives, to processes for their preparation and to intermediates used in these processes.

More specifically, the present invention relates to novel pyranoindole and thiopyranoindole derivatives possessing valuable pharmacologic properties. For example, these derivatives exhibit useful antidepressant properties at dosages which do not elicit undesirable side effects. Furthermore the present derivatives exhibit properties useful for the treatment and prevention of ulcers. The combination of these pharmacologic properties together with a low order of toxicity render the pyranoindoles and thiopyranoindoles of the invention therapeutically useful.

2. Description of the Prior Art

Only a rather limited number of reports dealing with pyranoindole darivatives are available. In the few that do exist, pyranoindoles are treated more in the manner of chemical curiosities. For the most part these reports discuss the preparation of pyranoindoles in which the pyran portion thereof exists as a lactone. For example, see H. Plieninger, Chem. Ber., 83, 271 (1950), S. Sakurai and T. Ito, Nippon Kagaku Zasshi, 78, 1665 (1957); [Chem Abstr., 54, 1488f (1960)], and J. Szmuszkovicz, J. Org. Chem., 27, 511 (1962).

The thiopyranoindoles of the prior art, for example, 5-(3-aminopropyl)-1,3,4,5-tetrahydrothiopyrano[4,3-b]indole, M. E. Freed, et al., J. Med. Chem., 7, 628 (1964) are distinguished from the present compounds of this invention by lacking substituents on the thiopyran ring.

SUMMARY OF THE INVENTION

The pyranoindole and thiopyranoindole derivatives of this invention are characterized by having an amino(lower)alkyl radical attached to a pyranoindole or thiopyranoindole nucleus. The preferred derivatives of this invention are represented by formula I and Ia ##STR1## in which R¹ is lower alkyl or lower cycloalkyl; R², R³, R⁴ and R⁵ are the same or different selected from the group consisting of hydrogen and lower alkyl; R⁶ is hydrogen, lower alkyl hydroxy, lower alkoxy, lower alkanoyloxy, nitro or halo; R⁷ is hydrogen, lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk--NR⁸ R⁹ wherein Alk is an alkylene selected form the group consisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰,R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are either the same or different selected from the group consisting of hydrogen and lower alkyl, or R⁸ is lower alkyl and R⁹ is p-chlorophenacyl or R⁸ and R⁹ together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, piperazino, 4-(lower-alkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl-1-piperazinyl; X is oxy or thio; and Y is lower alkyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk-NR⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are as defined herein; with the provisos that at least one of R⁷ and Y is -Alk-NR⁸ R⁹ and that in the compounds of formula Ia, Y must be --Alk-NR⁸ R⁹ as defined herein.

In the above definitions it is understood that Alk, R⁸ and R⁹ in each case are entitled to the full range of their definitions as listed above, so that Alk, R⁸ and R⁹ of Alk-NR⁸ R⁹ linked to position 9 of formula I need not necessarily be the same as Alk, R⁸ and R⁹ of Alk-NR⁸ R⁹ linked to position 1.

Various processes for the preparation of the compounds of formula I are disclosed.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-methylpentyl and the like.

The term lower alkyl as used herein contemplates both straight and branched chain alkenyl radicals containing from two to six carbon atoms and includes vinyl, allyl, 1-propenyl, methallyl, 2-ethyl-3-butenyl and from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-methylpentyl and the like.

The term "lower alkenyl" as used herein contemplates both straight and branched chain alkenyl radicals containing from two to six carbon atoms and includes vinyl, allyl, 1-propenyl, methallyl, 2-ethyl-3-butenyl and the like.

The term "phenyl(lower)alkyl" as used herein contemplates a phenylalkyl radical in which the alkyl portion thereof contains from one to four carbon atoms and includes benzyl, phenethyl, α-methylphenethyl and the like.

The term "lower cycloalkyl" as used herein contemplates saturated cyclic hydrocarbon radicals containing from three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term "lower alkoxy" as used herein contemplates both straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, isopropoxy and the like.

The term "lower alkanoyloxy" as used herein contemplates both straight and branched chain alkanoyloxy radicals containing from two to six carbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and the like.

The term "halo" as used herein contamplates halogens and includes fluorine, chlorine, bromine and iodine.

The compounds of this invention are capable of forming acid addition salts with pharmaceutically acceptable acids. Such acid addition salts are included within the scope of this invention.

The acid addition salts are prepared by reacting the base form of the appropriate compound of formula I or Ia with either one to four equivalents, depending on the number of basic nitrogens in the compound, or preferably with an excess of the appropriate acid in an organic solvent, for example, ether or an ethanol-ether mixture. These salts, when administered to mammals, possess the same pharmacologic activities as the corresponding bases. For many purposes it is preferable to administer the salts rather than the base compounds. Among the acid addition salts suitable for this purpose are salts such as the sulfate, phosphate, lactate, tartrate, maleate, citrate, hydrobromide and hydrochloride. Both the base compounds and the salts have the distinct advantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochemical isomers of the compounds of formulae I and Ia which result from asymmetric centers, contained therein. These isomeric forms are prepared by different methods and are purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractional crystallization of the diastereoisomeric salts formed thereof, for instance, with d- or 1- tartaric acid or D-(+)-α-bromocamphor sulfonic acid, are also included.

Antidepressant Activity

The useful antidepressant activity of the compounds of formulae I and Ia and their acid addition salts with pharmaceutically acceptable acids are demonstrated in standard pharmacologic tests, such as, for example, the tests described by F. Hafliger and V. Burckhart in "Psychopharmacological Agents," M. Gordon, Ed., Academic Press, New York and London, 1964, pp. 75 - 83.

More specifically, as noted in the latter reference the antidepressant properties of a compound may be demonstrated by its capacity to antagonize the depressant effects of reserpine. Furthermore, it is well documented that reserpine in animals produces a model depression which can be used for detecting antidepressant properties. Accordingly, the compounds of the present invention antagonize reserpine effects in mice at doses ranging from about 1 to 100 mg/kg. Several of the preferred compounds, for instance,

1-[(2-dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole oxalate (Example 309),

1-methyl-[3-(methylamino)propyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole oxalate (Example 310),

1-[3-(dimethylamino)propyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole oxalate (Example 312),

1-[2-(dimethylamino)ethyl]-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole maleate (Example 330),

1-[2(-dimethylamino)ethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole maleate (Example 683), and

1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole hydrochloride (Example 911), antagonize the effects of reserpine in mice at dose ranges from about 1 to 15 mg/kg.

When the compounds of this invention are used as antidepressants in warm-blooded mammals, e.g. rats and mice, they may be used alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are given at a concentration level that will afford an effective dose without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 0.1 mg to about 50 mg per kilo per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 0.5 mg to about 25 mg per kilo per day is most desirably employed in order to achieve effective results.

Antiulcer Activity

The compounds of this invention possess another useful pharmacologic property; that is, they are useful antiulcer agents. More particularly, the said compounds of this invention exhibit antiulcer activity in standard pharmacologic tests, for example, the test described by D. A. Brodie and L. S. Valitski, Proc. Soc. Exptl. Biol. Med., 113, 998 (1963), based on the prevention of stress-induced ulcers.

When these compounds are employed as antiulcer agents, they are formulated and administered in the same manner as described above for their use as antidepressant agents.

Processes

For the preparation of the pyranoindole and thiopyranoindole derivatives of formula I we prefer to use as starting materials the compounds of general formula II, ##STR2## in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in the first instance and X¹ is hydroxy, mercapto, --S--SO₃ -Na or --S--SO₃ K.

The starting materials of formula II in which X¹ is hydroxy are either known, for example, tryptophol, described by H. R. Snyder and F. J. Pilgrim, J. Am. Chem. Soc. 70, 3770 (1948), or they are obtained by the following process: ##STR3##

With reference to this process phenylhydrazines of formula III and the hydroxyaldehyde of formula IV are reacted together according to the conditions of the "Fischer Indole Synthesis," for example, see P. L. Julian, E. N. Myer and H. C. Printy, "Heterocyclic Compounds," R. C. Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc., New York, 1952, pp. 8 - 11, to form the desired starting material (II, X¹ = OH).

The phenylhydrazines of formula III are either known or are prepared according to known methods. A convenient method involves the diazotization of the appropriately substituted aniline to give the corresponding diazo derivative. The latter compound is then reduced with stannous chloride or sodium sulfite to give the corresponding phenylhydrazine, see L. F. Fieser and M. Fieser, "Advanced Organic Chemistry," Reinhold Publishing Corporation, New York, 1961, p. 734.

The hydroxyaldehydes of formula IV are either known, see for example, "Rodd's Chemistry of Carbon Compounds," S. Coffey, Ed., Vol. I d, 2nd ed., Elsevier Publishing Co., Amsterdam, 1965, pp. 44 - 49, or they are prepared according to known methods. A convenient method involves reduction of an appropriate lactone of formula ##STR4## with bis-(3-methyl-2-butyl)borane, H.G. Brown and D. B. Bigley, J. Am. Chem. Soc., 83, 486 (1961), diisobutyl aluminum hydride, L. I. Zakharkkin and I. M. Khorlina, Tetrahedron Letters, 619 (1962) or sodium aluminum hydride, L. I. Zakharkin et al., Tetrahedron Letters, 2087 (1963). The appropriate lactones utilized in this condensation are either commercially available, for example, δ-valerolactone, α-methyl-butyrolactone, or they are described with a variety of methods for their preparation in organic chemistry textbooks; such as the textbooks, "Methoden der Organischen Chemie," Houben-Weyl, E. Muller, Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561 - 852 or L. F. Fieser and M. Fieser, "Advanced Organic Chemistry," cited above.

Alternatively, the starting materials of formula II in which R² R³, R⁴ and R⁷ are hydrogen and X^(I) is hydroxy are prepared by lithium aluminum hydride reduction (N. G. Gaylord, "Reduction with Complex Metal Hydrides," Interscience Publishers, Inc., New York, 1956, pp. 322 - 370) of compounds of formula V described by T. Y. Shen, U.S. Pat. No. 3,161,654, Dec. 15, 1964: ##STR5## wherein R¹⁸ is lower alkyl and R⁵ and R⁶ are as defined in the first instance.

In addition, convenient processes are available for the specific synthesis of certain starting materials of formula II. For example, starting materials of formula -in which R², R³, R⁴, R⁵ and R⁷ are hydrogen and X^(I) is hydroxy are obtained by reduction of the appropriate ethyl 3-indoleglyoxylate with lithium aluminum hydride, British Patent 778,823 and T. Nogrady and T. W. Doyle, Can. J. Chem., 42, 485 (1964). Starting materials of formula II in which R² and R⁴ are hydrogen, R³, R⁵ and R⁷ are hydrogen or lower alky and X¹ is hydroxy are obtained by reacting indole or an appropriately substituted indole with ethylene oxide or lower alkyl substituted ethylene oxide according to the process of M. Julia et al., Bull. Soc. Chim. Fr., 2291 (1966).

The starting materials of formula II in which X¹ is mercapto, --S--SO₃ Na or --S--SO₃ K, and R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in the first instance are obtained by the following process: The appropriate compound of formula II (X^(I) =OH) described above, is treated with phosphorus tribromide in an inert solvent, for example, ether or methylene chloride- to afford the corresponding 3-(2-bromoethyl)-indole derivative. The latter compound is then converted to the desired starting material of formula II (X¹ = SH) by a procedure similar to that described by N. N. Suvorov and V. N. Buyonav, Khim.-Farm. Zh., 1, (1967), [Chem. Abstr. 67, 7347a (1967)], for converting 3-(2-bromoethyl)-indole to indole 3-ethanethiol (II; R², R³, R⁴, R⁵ and R⁶ = H and X¹ = SH). Accordingly, the appropriate 3-(2-bromoethyl)-indole derivative is treated with sodium or potassium thiosulfate to afford the corresponding sodium or potassium β-(3-indolyl)ethyl thiosulfate derivative, respectively: namely the desired starting materials of formula II (X=--S--SO₃ Na or --S--SO₃ K). Treatment of the latter product with strong alkali, for example, sodium or potassium hydroxide, yeilds the corresponding bis[ω-(3-indolyl)ethyl]-disulfide derivative. Reduction of the latter compound with lithium aluminum hydride gives the desired compounds of formula II (X¹ = SH).

Alternatively, the preceding thiosulfate derivative is treated with acid, for example, dilute aqueous solutions of hydrochloric acid, sulfuric acid or phosphoric acid, to give directly the latter compound of the formula II.

It should be noted that the preceding processes may not be entirely practical for the preparation of the compounds of formula II in which X^(I) is mercapto, --S--SO₃ Na or --S--SO₃ K, and R⁶ is hydroxy or lower alkanoyloxy. For this reason, the preferred starting materials of formula II for the ultimate preparation of the compounds of formula I in which R⁶ is hydroxy or lower alkanoyloxy and X is thio are the corresponding compounds of formula II in which R₆ is benzyloxy, i.e., a hydroxyl with a protecting benzyl group or other suitable protecting group, see J. F. McOmie, "Advances in Organic Chemistry," Vol. 3, R. A. Raphael, et al. Ed., Interscience Publishers, New York, 1963, pp. 191 - 294. When the latter compounds are used as starting materials in this manner, they are first subjected to the process (II + VI → VII), described below. Subsequently, the benzyloxy group is removed by hydrogenation, in the presence of a catalyst, for example, 10% palladium on carbon, just prior to affording the desired corresponding compound of formula I in which R⁶ is hydroxy. The latter are converted, if desired, to the corresponding compound of formula I in which R⁶ is lower alkanoyloxy by conventional means, for example, by treatment with the appropriate lower alkanoic anhydride preferably in the presence of pyridine. Likewise, it should be noted that similar use of the starting materials of formula II in which X¹ is hydroxy and R⁶ is benzyloxy to obtain the corresponding compound of formula I in which R⁶ is hydroxy or lower alkanoyloxy is also preferred.

The above described starting materials of formula II in which R², R³, R⁴, R⁵, R⁶, R⁷ and X¹ are as defined in the first instance are now subjected to a key reaction comprising the treatment of said starting materials with a compound of formula ##STR6## in which R¹ is as defined in the first instance and Z is selected from the group consisting of:

a. COOR¹⁹ and Alk¹ -COOR¹⁹ in which R¹⁹ is hydrogen or lower alkyl and Alk¹ is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are hydrogen or lower alkyl,

CONR⁸ R⁹ and Alk¹ -CONR⁸ R⁹ in which Alk¹, R⁸ and R⁹ are as defined above,

c. CH₂ OCOR²⁰ and Alk¹ -CH₂ OCOR²⁰ in which R²⁰ is hydrogen or lower alkyl and Alk¹ is as defined above,

d. Alk² -L in which Alk² is an alkylene selected from the group consisting of CR¹⁰ R¹¹ CHR¹², CR¹⁰ R¹¹ CR¹² R¹³ CHR¹⁴ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CHR¹⁶ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are as defined above and L is halo,

e. Alk NR⁸ COR²¹ in which Alk and R⁸ are as defined in the first instance and R²¹ is hydrogen or lower alkyl containing from one to five carbon atoms,

f. Alk - NO₂ in which Alk is as defined in the first instance,

g. Lower alkyl and phenyl(lower) alkyl, and

h. Alk --NR⁸ R⁹ in which Alk, R⁸ and R⁹ are as defined in the first instance, in the presence of an acid catalyst to yield the compounds of formula VII in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Z are as defined above. ##STR7##

Thereafter the appropriate compound of formula VII is converted to the desired pyranoindole of formula I according to the processes described hereinafter or is actually the desired compound of formula I in the case where Z is Alk--NR⁸ R⁹, as described above.

In practising the condensation (II + VI → VII) a solvent is used generally as a reaction medium. Any solvent inert to the reaction conditions may be used. Suitable solvents includes aromatic hydrocarbon, for example benzene, or toluene, ethers and cyclic ethers, for example diethyl ether, dioxan, or tetrahydrofuran, halogenated hydrocarbons, for example methylene dichloride, or carbon tetrachloride and the like. Benzene and tetrahydrofuran are especially convenient and practical for this use. A variety of suitable acid catalyst may be used for this condensation, for example, the type of catalyst used in a Friedel-Crafts reaction, i.e. p-toluenesulfonic acid, aluminum chloride, phosphorus pentoxide, boron trifluoride, zinc chloride, hydrochloric acid, perchloric acid, trifluoroacetic acid, sulfuric acid and the like. p-Toluenesulfonic acid, aluminum chloride, boron trifluoride and phosphorus pentoxide are included among the preferred acid catalysts. The amount of acid catalyst used is not especially critical and may range from 0.01 molar equivalents to 100 molar equivalents; however, a range of from 0.1 to 10 molar equivalents is generally preferred; however, note that the amount of acid catalyst should be in excess with respect to the basic nitrogens that may be present in R⁷ of the starting material of compound II or the compound of formula ##STR8## when Z is Alk-NR⁸ R⁹. The time of the reaction may range from10 minutes to 60 hours, with the preferred range being from one-half to 24 hours. The temperature of the reaction may range from 20° C. to the boiling point of the reaction mixture. Preferred temperature ranges include 20° to 120° C.

A more detailed description of the preparation of the above intermediate compounds of formula VII and a description of their subsequent conversion of pyranoindole and thiopyranoindole derivatives of formula I are disclosed below. For convenience these descriptions are categorized into sections according to the group selected for Z for the intermediate.

a. Preparation and Conversion of Intermediates of Formula VII (Z = COOR¹⁹ and Alk¹ -COOR¹⁹)

Intermediates of formula VII (Z = COOR¹⁹ and Alk¹ -COOR¹⁹ in which R¹⁹ is hydrogen or lower alkyl and Alk¹ is as defined in the first instance, R⁷ is hydrogen and R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance) are readily obtained by the condensation (II+VI→VII) by using ketoacids or ketoesters of formula ##STR9## in which R¹ is as defined in the first instance and Z is COOR¹⁹ or Alk¹ -- COOR¹⁹ as defined above together with the starting material of formula II (R⁷ = H).

Generally comparable yields of product are obtained in this process when either the ketoacid or the corresponding ketoester is used. However, in the case where it is desired to prepare an acid compound of formula VII(R⁷ = H) in which Z is Alk¹ COOR¹⁹ wherein Alk¹ is CR¹⁰ R¹¹ and R¹⁹ is hydrogen (i.e., an acid intermediate of formula VII), it is preferable to first condense the appropriate β-ketoester of formula VI rather than the corresponding β-ketoacid and then hydrolyze the resulting ester product to give the desired acid compound.

Moreover, in the general practise of this invention it is often more convenient to prepare the acid compounds of formula VII(R⁷ =H) by using the ketoester instead of the ketoacid in this process and then hydrolyze the resulting ester product to the desired acid, the reason being simply that the ketoesters are generally more readily available either commercially or by synthesis.

The hydrolysis of compounds of formula VII(R⁷ =H) in which Z is COOR¹⁹ or Alk¹ COOR¹⁹ wherein Alk¹ is as defined in the first instance and R¹⁹ is lower alkyl, i.e. ester intermediates of formula VII(R⁷ =H), to their corresponding acids of formula VII (R⁷ =H) is readily effected by treatment with a suitable alkali, for example, potassium hydroxide or sodium carbonate, in aqueous methanol or aqueous ethanol or by treatment with lithium iodide in a suitable organic solvent, for example, collidine, see L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis," John Wiley and Sons, Inc., New York, 1967, pp. 615 - 617.

The α-, β-, γ- and δ- ketoacids and -ketoesters of formula VI are either known, for example, ethyl pyruvate, levulinic acid, ethyl α,α-dimethylacetoacetate, and β,β-dimethyllevulic acid, or they are prepared by known methods described in general organic chemistry textbooks. For example, a comprehensive review on the properties and preparation of such α-, β-, γ- and δ-ketoacids and -ketoesters may be found in "Rodd's Chemistry of the Carbon Compounds," cited above, Vol. Id, pp. 226 - 274.

Thereafter these intermediate acids and esters of formula VII(R⁷ = H) are converted to compounds of formula I in which R¹, R², R³, R⁴, R⁵ R⁶ R⁷ and X are as defined in the first instance and Y is --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk¹ ---CH₂ wherein Alk¹ is as defined in the first instance and R⁸ and R⁹ are as defined in the first instance. This conversion is accomplished by amidation, reduction and if desired N-alkylation of the indolic nitrogen. The order of these steps is not critical. However, we have found the following sequence of these steps to be both convenient and practical.

First, when it is desired to prepare the derivatives of the latter group of compounds of formula I in which R⁷ is H, i.e., N-alkylation of the indolic nitrogen is not desired, either the above acid intermediate or ester intermediate may be employed.

In the case where the acid intermediate of formula VII(R⁷ = H) is employed, said acid is subjected to amidation by treatment with a lower alkyl chloroformate, preferably ethyl chloroformate, in the presence of triethylamine, affording the corresponding mixed anhydride, which is converted by treatment with the appropriate amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance, for example, ammonia, methylamine or dimethylamine, to yield the corresponding amide of formula VII in which Z is CONR⁸ R⁹ or Alk¹ CONR⁸ R⁹ in which Alk¹, R⁸ and R⁹ are as described in the first instance.

Alternatively, the latter amides are also obtained by treating the ester intermediates of formula VII (R⁷ =H) with the appropriate amine according to known amidation methods, for example, see A. L. F. Beckwith in "The Chemistry of Amides," J. Zalicky, Ed., Interscience Publishers, New York, 1970, pp. 96 - 105.

Secondly, the amides so obtained are reduced with a suitable complex metal hydride to yield the desired pyranoindoles and thiopyranoindoles. Examples of suitable complex metal hydrides are lithium aluminum hydride, lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borohydride-aluminum chloride. Lithium aluminum hydride is preferred.

On the other hand when it is desired to prepare the compounds of formula I of the above group in which R¹, R², R³, R⁴, R⁵, R⁶ are as defined in the first instance, R⁷ is lower alkyl, or lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl and Y is --Alk-N R⁸ R⁹ in which Alk is CH₂ or Alk¹ CH₂ wherein Alk¹ is as defined in the first instance and R⁸ and R⁹ are as defined in the first instance, the acid or ester intermediate of formula VII(R⁷ = H) are first subjected to N-alkylation by treatment with a molar excess of the appropriate organic halide, namely a lower alkyl halide, lower alkenyl halide, propargyl halide, phenyl(lower)alkyl halide or amino(lower)alkyl halide, respectively, in an inert solvent in the presence of a proton acceptor. Suitable inert solvents include tetrahydrofuran, benzene, toluene and dimethylformamide. Suitable proton acceptors include sodium hydride, alkali metal carbonate and triethylamine. Preferred conditions for effecting this N-alkylation include the use of sodium hydride as a proton acceptor and tetrahydrofuran as an inert solvent. Although the optimum temperature and reaction time will vary depending on the reactants employed, the reaction is generally performed at the boiling point of the reaction mixture for a period of 30 minutes to 48 hours.

The lower alkyl halides, lower alkenyl halides, propargyl halide, phenyl(lower)alkyl halides and aminoalkyl(lower)halides employed herein are either known, for example, ethyl bromide, allyl bromide and dimethylaminoethyl chloride, or they are prepared by known methods, usually by the treatment of the corresponding alcohols with a halogenating agent, for instance, thionyl chloride, see D. J. Collins and J. J. Hobbs, Aust. J. Chem., 20, 1413 (1967) and R. B. Moffett J. Org. Chem. 14, 862 (1949).

In this manner, the corresponding N-alkylated derivatives of the above acid and ester derivatives of formula VII are obtained. Thereafter these derivatives are subjected to the amidation and reduction steps according to the conditions described hereinabove in this section, to afford the desired compounds of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl, or amino(lower)alkyl.

Although the above sequence of steps for the conversion of the acid and ester intermediates of formula VII (R⁷ = H) to the above desired pyranoindoles is convenient and efficacious, a change in the order of the steps whereby the amides of formula VII (R⁷ = H) are treated with the appropriate organic halide according to the N-alkylation conditions described above, followed by reduction with a complex metal hydride, as described above, also affords the above desired compounds of formula I, in which R⁷ is lower alkyl, lower alkenyl, propargly, phenyl(lower)alkyl or amino(lower)alkyl. Treatment as described above, of the resulting corresponding amide derivative in which the indolic nitrogen is alkylated, also affords the above desired compounds of formula I, in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower) alkyl or amino(lower)alkyl.

Furthermore, another change in the order of the steps for preparing the latter compounds of formula I is realized by N-alkylation, as described above, of the corresponding compounds of formula I in which R⁷ is hydrogen, described above. In this case when the starting material employed is a pyranoindole or thiopyranoindole of formula I in which Y is --Alk-NR⁸ R⁹ in which Alk is CH₂ or Alk¹ -CH₂ wherein Alk¹ is as defined in the first instance and R⁸ is hydrogen and R⁹ is hydrogen or lower alkyl, i.e., a primary or secondary amine function is present in the molecule in addition to the indolic nitrogen, it is expedient to use only one molar equivalent of the appropriate organic halide to avoid alkylation of the primary or secondary amine if so desired.

Another aspect of the present intermediates of formula VII relates to their conversion to compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶,R⁷ and X are as described in the first instance and Y is -Alk-NR⁸ R⁹ in which Alk is CH₂ or ALk¹ CH₂ wherein Alk¹ is as defined in the first instance and R⁸ is hydrogen and R⁹ is lower alkyl, i.e. secondary amines. When it is desired to prepare the latter compounds a modification involving the protection of the secondary amine with a benzyl group or other suitable protecting group, see J. F. McOmie, cited above is especially convenient. For example, the aforementioned acid or ester intermediate of formula VII is reacted with an amine of formula HNR⁸ R⁹ in which R⁸ is benzyl and R⁹ is lower alkyl according to the amidation step described above. The resulting amide is N-alkylated on the indolic nitrogen, if desired, and then reduced with a complex metal hydride according to the above procedures. Thereafter the benzyl group is removed by hydrogenolysis in the presence of a catalyst, preferably 10% palladium on carbon, to afford the desired secondary amine compounds of formula I.

Still another modification relates to a more general reduction of the above amides of formula VII in which Z is CONR⁸ R⁹ or Alk¹ -CONR⁸ R⁹ wherein Alk¹, R⁸ and R⁹ are as defined in the first instance. In other words this modification is applicable to the reduction of tertiary, secondary and primary amides, described herein, and is a preferred modification for the reduction of the latter two. In practising this modification, the aforementioned amide of formula VII is treated with triethyloxonium fluoroborate or dimethyl sulfate, see H. Bredereck, et al., Chem. Ber., 98, 2754 (1965), in an inert solvent, for example, methylene dichloride, whereby the corresponding iminoether fluoroborate or methyl sulfate salt is obtained, respectively. Subsequent reduction of the salt thus obtained with a complex metal hydride, similar to the reduction described previously for the amides, yields the corresponding compounds of formula I. Alternatively, the above fluoroborate or methyl sulfate salt derived from a secondary or primary amide is decomposed by base treatment, for example, with 10% sodium hydroxide or triethylamine, to give the corresponding iminoether which is then reduced in a like manner to the desired compounds of formula I.

When applying the aforementioned steps in the preparation of compounds of formula I in which R⁶ is hydroxy or lower alkanoyloxy, it is preferable to use corresponding intermediates in which R⁶ is benzyloxy followed by the appropriate transformations as noted previously to yield the desired compounds of formula I.

b. Preparation and Conversion of Intermediates of Formula VII (Z = CONR⁸ R⁹ and Alk¹ -CONR⁸ R⁹).

The intermediates of formula VII in which R⁷ is hydrogen and Z is CONR⁸ R⁹ and Alk¹ --CONR⁸ R⁹ wherein R⁸, R⁹ and Alk¹ are as defined in the first instance, described in the previous section, are also obtained directly by utilizing the appropriate starting materials of formula II and α,β, γ- or δ-ketoamides of formula ##STR10## in which R¹ is as defined above and Z is CONR⁸ R⁹ or Alk¹ -CONR⁸ R⁹ in which Alk¹, R⁸ and R⁹ are as defined above. The ketoamides required for this condensation are either known, for example, pyruvamide or α,α-dimethylacetoacetamide, or they are prepared by known methods, for instance, see Rodd's Chemistry of the Carbon Compounds, cited above, Vol. 1d, pp. 226-274.

Thereafter these amides are converted by the reduction process, described above, to the compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, and X are as defined in the first instance, R⁷ is hyrogen and Y is --Alk-NR⁸ R⁹ in which Alk is CH₂ or Alk¹ --CH₂ wherein Alk¹ is as defined in the first instance and R⁸ and R⁹ are as defined in the first instance.

c. Preparation and Conversion of Intermediates of Formula VII (Z = CH₂ OCOR²⁰ and Alk¹ --OCOR²⁰)

Intermediates of formula VII in which R⁷ is hydrogen and Z is CH₂ OCOR²⁰ and Alk¹ --CH₂ OCOR²⁰ in which Alk¹ and R²⁰ are as defined in the first instance, are obtained when a starting material of formula II (R⁷ =H) is condensed with a ketoalcohol lower alkanoic acid ester of formula R¹ COCH₂ OCOR²⁰ or R¹ -CO-Alk¹ ---CH₂ OCOR²⁰ in which R¹, Alk¹ and R²⁰ are as defined in the first instance in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II + VI →VII). The ketoalcohol lower alkanoic acid esters are either known, for example, acetonyl acetate or 5-acetoxypentan-2-one, or are prepared by known methods, for instance, see Rodd's Chemistry of the Carbon Compounds, cited above, Vol. 1d, pp. 49-54.

These intermediates of formula VII may then be utilized for the preparation of compounds of formula I of this invention in the following manner. The intermediate is hydrolyzed with an aqueous alcoholic solution of a suitable alkali, for example, sodium hydroxide in aqueous methanol to afford the corresponding primary alcohol. The primary alcohol is then oxidized to the corresponding aldehyde. Although a variety of methods are known for the oxidation of a primary alcohol to its corresponding aldehyde, see for example, Rodd's Chemistry of the Carbon Compounds, cited above, Vol. 1c, pp. 4 - 10, we have found that the method of K. E. Pfitzner and J. G. Moffat, J. Am. Chem. Soc. , 87, 5670 (1965), using N,N-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of a suitable acid, for example, trifluoroacetic acid, is both efficacious and convenient. Thereafter the aldehyde is reacted with an amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance according to the method of K. N. Campbell, et al., J. Amer. Chem. Soc., 70, 3868 (1948) in the case when the amide used is ammonia or a primary amine or according to the method of N. J. Leonard and J. V. Paukstelis, J. Org. Chem., 28, 1397 (1963) when the amine is a secondary amine to give the corresponding Schiff base or ammonium salt, respectively. The product so obtained is reduced with sodium borohydride, see E. Schenker, Angew, Chem., 73, 81 (1961), to yield compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is hydrogen and Y is -Alk-NR⁸ R⁹ in which Alk is CH₂ or Alk¹ --CH₂ and R⁸ and R⁹ are as defined in the first instance.

Alternatively, the latter compounds of formula I are obtained by converting the above corresponding alcohol to a reactive intermediate such as the corresponding halide, mesylate or tosylate, which are then reacted with a two molar excess of an amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance. Preferably this reaction is performed in a suitable inert solvent, for example, tetrahydrofuran, at the boiling point of the reaction mixture for a period of eight to 24 hours. In connection with alkylations of amines of formula HNR⁸ R⁹ in which R⁸ is hydrogen and R⁹ is lower alkyl as disclosed herein, it is generally preferable to perform the alkylation with the corresponding N-benzyl derivative of said amine, i.e., an amine of formula HNR⁸ R⁹ in which R⁸ is benzyl and R⁹ is lower alkyl. Thereafter, when all appropriate transformation have been performed, the N-benzyl group is removed by hydrogenolysis with a catalyst, preferably 10% palladium on carbon, to give the desired compounds of formula I.

Thereafter, and if desired, these latter compounds of formula I are converted to their corresponding derivatives in which R⁷ is lower alkyl, lower alkenyl propargyl phenyl(lower) alkyl or amino(lower)alkyl by N-alkylation with one molar equivalent of the appropriate organic halide in the manner described for the N-alkylation in section (a).

Alternatively, the above aldehyde is oxidized with a suitable oxidizing agent to yield the corresponding acid intermediates of formula VII (R⁷ = H) described in section (a). Although a variety of suitable oxidizing agents may be used for this purpose, for example, silver oxide, alkaline permanganate, hydrogen peroxide, we prefer to use silver oxide according to the method of M. Delepine and P. Bonnet, Compt. rend., 149, 39 (1909).

Again alternatively, the above aldehyde is converted to its oxime which on reduction with a complex metal hydride yields the corresponding primary amine of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is hydrogen an Y is --Alk--NR⁸ R⁹ in which Alk is CH₂ or Alk¹ -CH₂ wherein Alk¹ is as defined in the first instance and R⁸ and R⁹ are hydrogen.

If desired these latter primary amine compounds of formula I may be N-alkylated on the indolic nitrogen in the manner described above with a molar equivalent of the appropriate organic halide to give the corresponding compounds of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or Alk:NR⁸ R⁹ wherein Alk, R⁸ and R⁹ are as defined in the first instance.

In turn these latter compounds of formula I may be further N-alkylated on the nitrogen of the primary amine with the appropriate lower alkyl halide to the corresponding compounds of formula I in which Y is --Alk-NR⁸ R⁹ wherein Alk is CH₂ or Alk¹ --CH₂ wherein Alk¹ is as defined in the first instance and R⁸ is hydrogen or lower alkyl and R⁹ is lower alkyl (i.e. secondary or tertiary amines with respect to Y). In this case depending on the particular derivative desired the N-alkylation is effected with one or two moles of the alkyl halide to give respectively the secondary (R⁸ = H and R⁹ = lower alkyl with respect to Y) or tertiary amine (R⁸ = R⁹ = lower alkyl with respect to Y). On the other hand the N-alkylation may be effected in two steps introducing a different alkyl group each time to afford the corresponding tertiary amine in which R⁸ and R⁹ are different lower alkyls with respect to Y.

When it is desired to prepare the above tertiary amine compounds in which R⁸ or R⁹ are either or both methyl, an alternative alkylation method comprises reacting the appropriate corresponding primary or secondary amine with an aqueous mixture of a substantial excess of formaldehyde and formic acid according to the conditions of the Eschweiler-Clarke reaction, see M.L. Moore, Organic Reactions, 5,301 (1949), whereby N-methylation is effected.

Another N-alkylation method which is applied to the above primary and secondary amines involves acylation with a lower alkanoic anhydride or acid halide and subsequent reduction of the resulting amide.

Furthermore, the above primary amines are used to prepare compounds of formula I in which Y is -Alk-NR⁸ R⁹ wherein Alk is CH₂ or Alk¹ --CH₂ and R⁸ and R⁹ together with the nitrogen atom to which they are joined form a heterocyclic amine radical as defined in the first instance. When used in this manner the primary amines are subjected to known N-alkylation methods, for example, see method J in Moffet, cited above, with the appropriate α,ω-dibromides, or α,ω-dibromides, for example, tetramethylene dibromide, pentamethylene dibromide bis(2-chloroethyl)ether, bis(2-chloroethyl)benzylamine followed by hydrogenation in the presence of 10% palladium on carbon to remove the protecting benzyl group, a bis(2-chloroethyl)lower alkylamine or a bis(2-chloroethyl)-N-[hydroxy(lower)-alkylamine, to give the corresponding, desired compound of formula I wherein Y is an amino(lower)alkyl in which the amino portion thereof is pyrrolidino, piperidino, morpholino, piperazino, 4-(lower)alkyl-1-piperazinyl or 4-[hydroxy-(lower)alkyl]-1-piperazinyl, respectively.

If during the above N-alkylations it is desired to protect primary or secondary amine functions that are present in the R⁷ portion of compounds of formula I, such protection may be afforded by the use of appropriate protecting groups, for example, a benzyl group; see also, J.F.W. McOmie in "Advances in Organic Chemistry Vol. 3, R. A. Raphael, et al., Ed., Interscience Publishers, New York, 1963, pp. 191-294.

d. Preparation and Conversion of Intermediates of Formula VII (Z - Alk² --L).

Intermediates of formula VII in which R⁷ is hydrogen and Z is alk² -L wherein Alk² and L are as defined in the first instance, are obtained when a starting material of formula II (R⁷ =H) is condensed with a β,γ- or δ-haloketone of formula R¹ CO--Alk² --L in which R¹, Alk² and L are as defined in the first instance in the presence of a suitable acid catalyst according to the conditions described above for the condensation (II + VI→VII). The haloketones are either known, for example, 4-chlorobutan-2-one, or they are prepared by known methods, for instance, see Rodd's Chemistry of Carbon Compounds, cited above, Vol. 1 c, pp. 70-71 and Methoden der Organischen Chemie Houben-Weyl, E. Muller, Ed., Vol. V/3, Georg Thieme Verlag, Stuttgart, 1962, pp. 511-1076.

Thereafter these intermediates of formula VII are treated with a two molar excess of an amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance to yield the compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as described in the first instance, R⁷ is hydrogen and Y is -Alk-NR⁸ R⁹ in which Alk is Alk² as defined in the first instance and R⁸ and R⁹ are as defined in the first instance. Preferred conditions for this reaction include the use of a suitable inert solvent, for example, tetrahydrofuran, temperatures ranging from 40° - 100° C. or at the boiling point of the reaction mixture and a reaction time of from eight to 24 hours.

If desired the latter pyranoindoles and thiopyranoindoles may be N-alkylated on the indolic nitrogen with an appropriate lower alkyl halide or aminoalkyl halide according to the method described for the N-alkylation of the pyranoindoles and thiopyranoindoles in section (a).

e. Preparation and Conversion of Intermediates of Formula VII (Z = AlkNR⁸ COR²¹)

Intermediates of formula VII in which R⁷ is hydrogen and Z is AlkNR⁸ CR²¹ wherein Alk, R⁸ and R²¹ are as defined in the first instance are readily obtained by the condensation (II + VI→VII) by using ketoamides of formula ##STR11## in which R¹, Alk, R⁸ and R²¹ are as defined in the first instance together with the appropriate starting material of formula II (R⁷ = H).

The ketoamides used herein are either known, for example, formamidoacetone [A. Treibs and W. Sutter, Chem. Ber., 84, 96 (1951)] and see[R.H. Wiley and O.H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948)] or they are prepared by known procedures, for example, see Methoden der Organischen Chemie, cited above, Vol. XI1, 1957, especially pp. 58-62, 285-289 and 508-509, and F.F. Blicke, Organic Reactions, 1, 303 (942).

Thereafter, reduction with a complex metal hydride and if desired N-alkylation of the indolic nitrogen as described in section (a) converts the instant intermediates of formula VII to pyranoindoles of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X are as defined in the first instance and Y is AlkNR⁸ R⁹ in which Alk and R⁸ are as defined in the first instance and R⁹ is lower alkyl.

f. Preparation and Conversion of Intermediates of Formula VII (Z = Alk -- NO₂)

Intermediates of formula VII in which R⁷ is hydrogen and Z is Alk-NO₂ wherein Alk is as defined in the first instance, are obtained by the condensation (II + VI→VII) when the starting materials of formula II (R⁷ = H) and appropriate α-, β-, γ-, and δ-nitroketones of formula ##STR12## in which R¹ and Alk are as defined in the first instance are employed therein in the presence of a suitable acid catalyst. In this case trifluoroacetic acid is the preferred acid catalyst.

The nitroketones used herein are either known, for example, 1-nitro-2-propanone, N. Levy and C.W. Scaife, J. Chem. Soc., 1100, (1946) and 5-nitro-2-hexanone, H. Shechter, et al., J. Amer. Chem. Soc. 74, 3664 (1952) or they are prepared by known methods, for example, see Levy, and Scaife, cited above, Shechter, et al. cited above, Rodd's Chemistry of carbon Compounds, cited above, Vol. 1c, pp. 71-72 and Methoden der Organischen Chemie, cited above, Vol,. X/1, 1971, p. 203.

Thereafter, these intermediates of formula VII are reduced with a complex metal hydride, preferably lithium aluminum hydride, to afford the pyranoindoles of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, Y is hydrogen and Z is --Alk-NR⁸ R⁹ in which Alk is defined in the first instance and R⁸ and R⁹ are hydrogen.

If desired the latter compounds may be N-alkylated according to the methods described in section (c) to give the compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and X are as defined in the firt instance and Y is Alk-NR⁸ R⁹ in which Alk, R⁸ and R⁹ are as defined in the first instance.

G. Preparation and Conversion of Intermediates of Formula VII (Z = lower alkyl or phenyl(lower)alkyl)

Intermediates of formula VII (Z = lower alky or phenyl(lower)alkyl, R⁷ is hydrogen and R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance) are readily obtained by the condensation (II + VI→VII) by using the starting materials of formula II and the ketones of formula ##STR13## in which R¹ is as defined in the first instance and Z is lower alkyl or phenyl(lower)alkyl.

The ketones used herein are either available commercially, for example, acetone or pheylacetone, or they are prepared by conventional methods, for example, see P. Karrer, "Organic Chemistry", 2nd. ed., Elsevier Publishing Co., Inc., New York, 1946, pp. 149-169 and V. Migrdichian, "Organic Synthesis," Vol. 1, Reinhold Publishing Corp., New York, 1957, pp. 100-129.

These intermediates of formula VII are converted to the compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is --(Alk)--NR⁸ R⁹ in which Alk, R⁸ and R⁹ are as defined in the first instance and Y is lower alkyl or phenyl(lower)alkyl by N-alkylation of the indolic nitrogen with the appropriate amino(lower)alkyl halide according to the method of N-alkylation described in section (a).

h. Preparation of Compounds VII Formula VII (Z = Alk-NR⁸ R⁹) .tbd. Compounds of Formula I (Y = Alk-NR⁸ R⁹)

The above described starting materials of formula II in which R², R³, R⁴, R⁵, R⁶, R⁷ and X¹ are as defined in the first instance are condensed in the presence of an acid catalyst with an aminoketone of formula R¹ CO--Alk-NR⁸ R⁹ in which R¹, Alk, R⁸ and R⁹ are as defined in the first instance to give directly the pyrano- and thiopyranoindole derivatives of formula I of this invention.

The requisite aminoketones for this reaction are either known, for example, 1-dimethylamino-3-butanone, 1-methylamino-3-petanone, see F.F. Blicke, cited above, or they may be prepared by known procedures, for example, see Methoden der Organischen Chemie, cited above, Vol, X1/1, 1957, pp. 58-62, 285-289 and 508-509.

In practising this present condensation it is generally advantageous to utilize substantially equimolar amounts of the starting material of formula II and the aminoketone in the presence of an acid catalyst. In this particular condensation the amount of the aforementioned. acid catalyst to employ ranges generally from about 1.01 to 100 molar equivalents with respect to the amount of aminoketone reactant, a range of from 105 to 10 molar equivalents being preferred. If more than one basic nitrogen is present in the reactants, for example, when R⁸ and R⁹ together with the nitrogen atom to which they are attached represent a piperazino radical, then additional acid catalyst is added to compensate for such basic nitrogens. Optionally, one may employ the acid addition salts of the aforementioned aminoketones and starting materials of formula II if R⁷ is an amino(lower)alkyl radical, for example the hydrochloride or the sulfate salt. In this case the amount of acid catalyst may range from 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents. Boron trifluoride is a preferred acid catalyst for the present condensation. The reaction may be performed conveniently and advantageously without a solvent, although a high boiling solvent, for example, toluene, o-xylene or isobutyl ether, may be used. When the solvent is omitted, it is desirable to heat the reactants to a melt and stir the melt in an inert atmosphere, for example, nitrogen or helium. Reaction time and temperature depends on the particular reactants employed and may be varied. The most convenient reaction time is from onehalf to 48 hours, preferably one-half to four hours, and reaction temperatures from 20° to 200° C, preferably 60 to 140° C. The reaction in each individual case is performed preferably at the lowest temperature at which the reaction proceeds smoothly and expeditiously with a minimum of decomposition.

In the case where the starting material is one of formula II in which Y is --S--SO₃ Na or --S--SO₃ K, it is preferable to have at least one equivalent of water present in the reaction mixture. This water may be added directly to the reaction or it may be included as part of the acid catalyst. Examples of the latter instance would be when p-toluenesulfonic acid containing water of crystallization of concentrated hydrochloric acid are employed as the acid catalyst.

With reference to the preparation of the pyranoindole and thiopyranoindole derivatives of formula Ia, the replacement of the starting material of formula II in any of the aforementioned processes (a) to (g) with the strting material of formula IIa, ##STR14## in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined in the first instance and X¹ is as defined in the first instance, give the corresponding intermediate of formula VIIa, ##STR15##in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X and Z are as defined hereinbefore. In the case where Z of said intermediate is Alk--NR⁸ R⁹, the intermediate is the pyranoindole or thiopyranoindole of formula Ia. In the case where Z of said intermediate is other than --Alk--NR⁸ R⁹, the intermediate is transformed to the corresponding pyranoindole of thiopyranoindole of formula Ia by the application of steps described hereinbefore for effecting the corresponding transformation of intermediates of formula VII to the compounds of formula I.

In other words the treatment of the starting material of formula IIa with a compound of formula ##STR16## in which R¹ and Z are as defined in the first instance according to the conditions of the condensation (II + VI→ VII), described hereinbefore, gives the corresponding intermediate of formula VIIa, the latter compound being the corresponding compound of formula Ia or an intermediate therefor.

The requisite starting material of formula IIa in which X¹ is hydroxy and R², R³, R⁴, R⁵, R⁶, and R⁷ is hydrogen is obtained by treating 2-(2-indolyl)ethyl tosylate, described by T. Saken, Tetrahedron Letters, 4925 (1968) with 10% sodium hydroxide solution. Optionally, th latter tosylate may be used in the condensation reaction in place of the starting material of formula IIa in which X¹ is hydroxy and R⁷ is hydrogen. The requisite starting material of formula IIa in which X¹ is hydroxy and R⁷ is defined in the first instance other than hydrogen is obtained by reacting the appropriately substituted indole, for example, N-methylindole, or N-ethylindole, with ethylene oxide or an appropriately substituted ethylene oxide according to the procedure of Julia, et al., cited above. The requisite starting material of formula IIa in which X¹ is mercapto, --S--SO₃ --Na or --S--SO₃ --K, are prepared from the above corresponding compounds of formula IIa in which X¹ is hydroxy according to the procedure described previously for the similar transformation of starting materials of formula II (X¹ = hydroxy) to starting materials of formula II (X¹ = mercapto --S--SO₃ Na or --S--SO₃ --K).

Finally, it is the intention to cover all changes an modifications of the embodiment of the invention herein chosen for the purpose of disclosure which are within the scope and spirit of this invention. Such changes and modification include those variations which depend on well known interconversions of amines, amides, acids and esters or alternation of the order of the steps in the processes disclosed herein.

For example, the act of subjecting the corresponding derivative of the starting material of formula II or IIa in which the indolic nitrogen is alkylated with a lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl, to condensation with an appropriate compound of formula VI according to the conditions of the key reaction taught in this present disclosure to yield the corresponding intermediate compound of formula VII or γIIa in which the indollic nitrogen is so alkylated would not depart from the scope or spirit of this invention.

More specifically exemplified, the compounds of formula I in which R⁷ is lower alkyl are prepared conveniently and generally in good yields by using the starting material of formula II in which R⁷ is lower alkyl and subjecting the starting material to treatment with the appropriate compound of formula ##STR17## and subsequent conversions, if necessary, according to the teachings of the present disclosure.

The following examples illustrate further this invention.

EXAMPLE I 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (VII: R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O AND Z = CH₂ COOH)

Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester, as an oil,γ_(max) ^(CHCl).sbsb.3 1715 cm⁻ ¹.

Hydrolysis of this ester to the title compound is effected as follows: The ester is dissolved in 230 ml. of methanol. To this is added 10 g. of KOH in 30 ml. of H₂ O and the solution is allowed to stand at room temperature overnight. The methanol is evaporated, water added and the solution washed with benzene. The aqueous phase is acidified with 6N HCl, and extracted with benzene. This organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give an oil, which is crystallized from benzene containing a trace of petroleum ether to afford the title compound, m.p. 150° - 152° C.,γ_(max) ^(CHCl).sbsb.3 3325 and 1705 cm⁻ ¹.

An equivalent amount of methyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indoleacetic acid methyl ester, m.p. 87°-90° C. after recrystallization from benzene-hexane, is obtained as the ester.

An equivalent amount of propyl acetoacetate may replace ethyl acetoacetate in the procedure of this Example. In this case, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid propyl ester is obtained as the ester.

EXAMPLE 2 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-PROPIONIC ACID (VII: R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H. X = O AND Z = CH₂ CH₂ COOH)

A mixture of the starting material of formula II, tryptophol (500 mg.), levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphorus pentoxide and about 0.5 g. of diatomaceous earth (Celite) is stirred magnetically at room temperature for 15 minutes and then at 70° C. for 11/2 hr. The reaction mixture is filtered. The filtrate is washed three times with 5N NaOH; the combined aqueous phase is washed twice with ether and then rendered acidic with cold 50% HCl. The aqueous phase is extracted with chloroform. The chloroform extract is dried (Na₂ SO₄) and evaporated to dryness. The residue is crystallized from ethyl acetate-petroleum ether to afford the title compound, m.p. 104°-110° C., nmr (CDCl₃) δ1.47 (3H), 2.18 (4H), 2.74 (2H), 3.96 (2H), 7.18 (4H), 7.85 (1H), 9.60 (1H).

The above title compound is also obtained by following the procedure of Example 1 but replacing ethyl acetoacetate with an equivalent amount of ethyl levulinate. In this case 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid ethyl ester, m.p. 116°-118° C.,γ_(max) ^(CHCl).sbsb.3 1716 cm⁻ ¹, after crystallization from benzene-petroleum ether, is obtained as the ester prior to hydrolysis.

EXAMPLE 3 1-METHYL-1,3,4,9-TETRAHYDROTHIOPYRANO[3,4-b]INDOLE-1-ACETIC ACID (VII: R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = S AND Z = CH₂ COOH)

Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70°-80° C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as a semi-solid,γmax^(CHCl).sbsb.3 1715 cm⁻ ¹.

This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in Examples 1 and 2 to afford the title compound, m.p. 147°-149° C., nmr (CDCl₃) δ1.86 (S, 3H), 3.06, 8.12 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), after recrystallization from benzene-hexane.

The procedures of Examples 1, or 3 are followed to prepare other compounds of formula VII in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is hydrogen and Z is COOR¹⁹ or Alk¹ --COOR¹⁹ wherein R¹⁹ and Alk¹ are as defined in the first instance. Examples of such compounds of formula VII are listed in Tables I and II. In each of these examples an equivalent amount of the starting material of formula II listed therein is used instead of the starting material of formula II described in the procedures of Examples 1 and 3. Note that in each of these examples the ester obtained prior to hydrolysis is a corresponding ester compound of formula VII.

Similarly, the procedure of Example 2 is used to prepare the products listed in Tables I and II. In this case an equivalent amount of the starting material of formula II, listed therein, is used instead of the starting material of formula II described in Example 2 and an equivalent amount of the corresponding ketoacid of formula VI is used instead of the ketoester of formula VI listed therein.

                                      TABLE I                                      __________________________________________________________________________      EX.                                                                               FORMULA IISTARTING MATERIAL OF                                                                       ##STR18##                                                                                            ##STR19##                      __________________________________________________________________________        R.sup.2                                                                            R.sup.3                                                                           R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                             X R.sup.1                                                                             Alk.sup.1CO  R.sup.19                                                                           PREFIX//SUFFIX                  __________________________________________________________________________      4 H   H  H   H   H    O CH.sub.3                                                                            CO           C.sub.2 H.sub.5                                                                    1-methyl//carboxylic                                                           acid                             5 CH.sub.3                                                                           H  H   H   H    O C.sub.2 H.sub.5                                                                     CO           C.sub.2 H.sub.5                                                                    1-ethyl-3-methyl//                                                             carboxylic acid                  6 n-C.sub. 3 H.sub.7                                                                 H  H   H   5-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CO           CH.sub.3                                                                           1,3-diisopropyl-6-                                                             methyl//carboxylic                                                             acid                             7 CH.sub.3                                                                           CH.sub.3                                                                          H   H   5-OH O CH.sub.3                                                                            CO           CH.sub.3                                                                           1,3,3-trimethyl-6-                                                             hydroxy//caboxylic                                                             acid                             8 H   H  H   H   7-C.sub.2 H.sub.5                                                                   O n-C.sub.3 H.sub.7                                                                   CO           CH.sub.3                                                                           8-ethyl-1-propyl//                                                             carboxylic acid                  9 H   H  i-C.sub. 3 H.sub.7                                                                 H   H    O                                                                                 ##STR20##                                                                          CO           CH.sub.3                                                                           1-cyclopropyl-4-isopro-                                                        pyl//carboxylic acid            10 CH.sub.3                                                                           CH.sub.3                                                                          C.sub.2 N.sub.5                                                                    C.sub.2 H.sub.5                                                                    H    O                                                                                 ##STR21##                                                                          CO           CH.sub.3                                                                           1-cyclopentyl-4,4-                                                             dietyl-3,3-dimethyl//                                                          carboxylic acid                 11 H   H  CH.sub.3                                                                           H   H    O CH.sub.3                                                                            CH.sub.2 CO  C.sub.2 H.sub.5                                                                    1,4-dimethyl//acetic                                                           acid                            12 H   H  H   H   H    O C.sub.2 H.sub.5                                                                     CH.sub.2 CO  C.sub.2 H.sub.5                                                                    1-etyl//acetic acid,                                                           m.p. 137 - 140° C.       13 H   H  H   H   H    O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                    1-propyl//acetic acid                                                          m.p. 148 - 151° C.       14 H   H  H   H   H    O i-C.sub.C.sub.3 H.sub.7                                                             CH.sub.2 CO  C.sub.2 H.sub.5                                                                    1-isopropyl//acetic                                                            acid, m.p. 150                                                                 - 152° C.                15 CH.sub.3                                                                           H  H   H   H    O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                    3-methyl-1-propyl//                                                            acetic acid;                                                                   m.p. 75 - 80° C.                                                        (Isomer A): m.p. 146 -                                                         148° C. (Isomer                                                         B).                             16 CH.sub.3                                                                           H  C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           H    O C.sub.2 H.sub.5                                                                     CH.sub.2 CO  C.sub.2 H.sub.5                                                                    1,4-diethyl-3-methyl//                                                         acetic acid,                    17 H   H  H   H   H    O CH.sub.3                                                                            CH(CH.sub.3)CO                                                                              C.sub.2 H.sub.5                                                                    α,1-dimethyl//acetic                                                     9                                                                              acid; m.p. 154                                                                 - 156° C.                                                               (Isomer A), m.p. 163 -                                                         165° C. (Isomer                                                         B).                             18 H   H  H   H   H    O                                                                                 ##STR22##                                                                          C(CH.sub.3).sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-cyclohexyl-α,.alpha                                                    .- dimethyl//acetic acid        19 H   H  H   H   H    O t-C.sub. 4 H.sub.9                                                                  CH.sub.2 CO  C.sub.2 H.sub.5                                                                    1-t-butyl//acetic acid,                                                        m.p. 210 - 212° C.       20 H   H  H   H   H    O n-C.sub. 4 H.sub.9                                                                  C.sub.2 H.sub.5                                                                             1-butyl//acetic acid.                                                              m.p. 124 - 127° C.       21 H   H  H   H   7-CH.sub.3                                                                          O n-C.sub. 3 H.sub.7                                                                  CH.sub.2 CO  C.sub.2 H.sub.5                                                                    8-methyl-1-propyl//                                                            acetic acid m.p. 127 -                                                         128° C.                  22 H   H  H   H   5-Br O C.sub.2 H.sub.5                                                                     CH.sub.2 CO  C.sub.2 H.sub.5                                                                    6-bromo-1-ethyl//                                                              acetic acid m.p.                                                               182 - 184° C.            23 H   H  H   H   5-OCH.sub.3                                                                         O CH.sub.3                                                                            CH.sub.2 CO  CH.sub.3                                                                           6-methoxy-1-methyl//                                                           acetic acid, m.p.                                                              142 - 143° C.            24 H   H  H   H   5-OCOCH.sub.3                                                                       O CH.sub.3                                                                            CH.sub.2 CO  C.sub.2 H.sub.5                                                                    6-acetoxy-1-methyl//                                                           acetic acid, m.p.                                                              142 - 143° C.            25 H   H  H   H   5-benzyl:                                                                           O CH.sub.3                                                                            CH.sub.2 CO  C.sub.2 H.sub.5                                                                    6-benzyloxy-1-methyl//                            oxy                          acetic acid, m.p.                                                              163.5° C.                26 H   H  H   H   4-CH.sub. 3                                                                         O n-C.sub. 3 H.sub.7                                                                  CH.sub.2 CO  C.sub.2 H.sub.5                                                                    5-methyl-1-propyl//                                                            acetic acid, m.p.                                                              177 - 178° C.            27 H   H  H   H   6-CH.sub. 3                                                                         O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO  C.sub.2 H.sub.5                                                                    7-methyl-1-propyl//                                                            acetic acid, m.p.                                                              157 - 158° C.            28 H   H  H   H   5-NO.sub. 2                                                                         O n-C.sub. 3 H.sub.7                                                                  CH.sub.2 CO  C.sub.2 H.sub.5                                                                    6-nitro-1-propyl//                                                             acetic acid, m.p.                                                              119 - 120° C.            29 H   H  CH.sub.3                                                                           CH.sub.3                                                                           H    O N-C.sub.C.sub.3 H.sub.7                                                             CH.sub.2 CO  C.sub.2 H.sub.5                                                                    4,4-dimethyl-1-                                                                propyl//acetic acid,                                                           m.p. 184 - 185° C.       30 CH.sub.3                                                                           CH.sub.3                                                                          H   H   5OC.sub.2 H.sub.5                                                                   O                                                                                 ##STR23##                                                                          CH(C.sub.2 H.sub.5)CO                                                                       C.sub.2 H.sub.5                                                                    1-cyclopropyl-α,.alph                                                    a.- diethyl-3,3-dimethyl-                                                      6-ethoxy//acetic acid           31 CH.sub.3                                                                           CH.sub.3                                                                          C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    6C.sub.2 H.sub.5                                                                    O                                                                                 ##STR24##                                                                          C(CH.sub.3).sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-cyclohexyl-α,.alpha                                                    .,3,3- tetramethyl-4,4,7-                                                      triethyl//acetic acid           32 CH.sub.3                                                                           H  n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  4-n-C.sub.3 H.sub.7                                                                 O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CO                                                                              C.sub.2 H.sub.5                                                                    α,3-dimethyl-1-ethyl-                                                    4,4,5-tripropyl//                                                              acetic acid                     33 H   H  H   H   H    O n-C.sub.3 H.sub.7                                                                   C(CH.sub.3).sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    α,α-dimethyl-1-                                                    propyl//acetic acid             34 C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    4-C.sub.2 H.sub.5                                                                   O t-C.sub.4 H.sub.9                                                                   C(i-C.sub.3 H.sub.7).sub.2 CO                                                               C.sub.2 H.sub.5                                                                    1-t-butyl-α,α-                                                     diisopropyl-3,3,4,4,5-                                                         pentaethyl//acetic                                                             acid                            35 H   H  H   H   4-I  O i-C.sub.3 H.sub.7                                                                   CH.sub.2 CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    5-iodo-1-isopropyl//                                                           propionic acid                  36 CH.sub.3                                                                           CH.sub.3                                                                          CH.sub.3                                                                           CH.sub.3                                                                            ##STR25##                                                                          O C.sub.2 H.sub.5                                                                     CH.sub.2 CH(CH.sub.3)CO                                                                     C.sub.2 H.sub.5                                                                    8-acetoxy-1-ethyl-                                                             α,3,3,4,4- pentamethy                                                    l// propionic acid              37 H   H  H   H   6-OH O n-C.sub.3 H.sub.7                                                                   CH.sub.2 C(C.sub.2 H.sub.5).sub.2 CO                                                        C.sub.2 H.sub.5                                                                    β,β,-diethyl-7-hy                                                    droxy-                                                                         1-propyl//propionic                                                            acid                            38 CH.sub.3                                                                           H  H   H   7-NO.sub.2                                                                          O                                                                                 ##STR26##                                                                          CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                            C.sub.2 H.sub.5                                                                    1-cyclobutyl-3-methyl                                                          8-nitro-α-propyl//                                                       propionic                       39 H   H  CH.sub.3                                                                           H   5-CH.sub.3                                                                          O                                                                                 ##STR27##                                                                          C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                         C.sub.2 H.sub.5                                                                    1-cyclopropyl-α,.alph                                                    a.,β,β,4,6-hexame                                                    thyl//propionic                                                                acid                            40 CH.sub.3                                                                           H  H   H   H    O CH.sub.3                                                                            CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                                         C.sub.2 H.sub.5                                                                    1,3-dimethyl-α,.alpha                                                    .-                                                                             dipropyl//propionic                                                            acid                            41 CH.sub.3                                                                           H  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H    O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)C(CH.sub.3).sub.2 CO                                                            CH.sub.3                                                                           α,α,β,3-te                                                    tramethyl-                                                                     1,4,4-triethyl//                                                               propionic acid                  42 H   H  CH.sub.3                                                                           CH.sub.3                                                                           H    O C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 CO                                                               CH.sub.3                                                                           1-ethyl-β,β,4,4-                                                     tetramethyl//propionic                                                         acid                            43 H   H  n-C.sub.3 H.sub.7                                                                  H                                                                                   ##STR28##                                                                          0                                                                                 ##STR29##                                                                          C(C.sub.2 H.sub.5).sub.2 C(C.sub.2 H.sub.5)C                                   O            CH.sub.3                                                                           1-cyclopentyl-5- propionoxy                                                    -4-propyl- α,β,.                                                    beta.-triethyl// propionic                                                     acid                            44 n-C.sub.3 H.sub.7                                                                  H  H   H   4-OCH.sub.3                                                                         O n-C.sub.3 H.sub.7                                                                   CH.sub.2 CH)CH.sub.3)CO                                                                     C.sub.2 H.sub.5                                                                    1,3-dipropyl-5-methoxy-                                                        α-methyl//propionic                                                      acid                            45 C.sub.2 H.sub.5                                                                    H  H   H   5-NO.sub.2                                                                          0 CH.sub.3                                                                            C(C.sub.2 H.sub.5).sub.2 C(C.sub.2 H.sub.5).                                   sub.2 CO     C.sub.2 H.sub.5                                                                    1-methyl-6-nitro-β,.be                                                    ta.,3-pentaethyl//                                                             propionic acid                  46 C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   H   H   4-C.sub.2 H.sub.5                                                                   O n-C.sub.3 H.sub.7                                                                   CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                            CH.sub.3                                                                           β,1-dipropyl-3,3,5-                                                       triethyl//propionic                                                            acid                            47 H   H  H   H   6-OC.sub.2 H.sub.5                                                                  O                                                                                 ##STR30##                                                                          CH(C.sub.2 H.sub.5)CH(C.sub.2 H.sub.5)CO                                                    C.sub.2 H.sub.5                                                                    1-cyclopropyl-α,.beta                                                    .- diethyl-7-ethoxy//                                                          propionic acid                  48 H   H  H   H   H    O CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 CO                                                               C.sub.2 H.sub.5                                                                    1-methyl//butyric acid,                                                        m.p. 132 - 135° C.       49 CH.sub.3                                                                           H  H   H   H    O C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CH.sub.2 CH.sub.2 CO                                                            C.sub.2 H.sub.5                                                                    γ,3-dimethyl-1-ethyl/                                                    /                                                                              butyric acid                    50 CH.sub.3                                                                           CH.sub.3                                                                          H   H   H    O n-C.sub.3 H.sub.7                                                                   C(C.sub.2 H.sub.5).sub.2 CH.sub.2 CH.sub.2                                     CO           C.sub.2 H.sub.5                                                                    γ,γ-diethyl-3,3                                                    -                                                                              dimethyl-1-propyl//                                                            butyric acid                    51 CH.sub.3                                                                           CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                  H   H    O                                                                                 ##STR31##                                                                          C(n-C.sub.3 H.sub.7).sub.2 CH(n-C.sub.3                                        H.sub.7)CH.sub.2 CO                                                                         C.sub.2 H.sub.5                                                                    1-cyclobutyl-3,3- dimethyl-                                                    β,γ,γ,4-                                                      tetrapropyl//butyric acid       52 H   H  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    6-Cl O CH.sub.3                                                                             ##STR32##   C.sub.2 H.sub.5                                                                    7-chloro-α,β,.be                                                    ta.,γ,γ,4,                                                         heptaethyl-1-methyl//                                                          butyric acid                    53 H   H  CH.sub.3                                                                           H   4-CH.sub.3                                                                          O C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2 ].sub.3 CO                                                               C.sub.2 H.sub.5                                                                    1-ethyl-α,α,.be                                                    ta.,β,γ,γ,                                                    4,                                                                             4,5-octamethyl//                                                           butyric acid                        54 C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    H                                                                                   ##STR33##                                                                          O n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)[C(C.sub.2 H.sub.5)].sub.                                   2 CO         C.sub.2 H.sub.5                                                                    6-acetoxy-α,α,.                                                    beta.,β,γ,3,                                                        3,4-octaethyl-1-propyl                                                         butyric acid                    55 H   H  CH.sub.3                                                                           CH.sub.3                                                                           7-OCH.sub.3                                                                         O                                                                                 ##STR34##                                                                          CH.sub.2 [C(CH.sub.3).sub.3 ].sub.2                                                         C.sub.2 H.sub.5                                                                    1-cyclobutyl-α,.alpha                                                    .,β,β- 4,4-hexame                                                    thyl-8- methoxy//butyric                                                       acid                            56 H   H  H   H   4-Br O                                                                                 ##STR35##                                                                          CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                                      C.sub.2 H.sub.5                                                                    5-bromo-1-cyclopenty-                                                          α,α,β-trim                                                    ethyl// butyric acid            57 CH.sub.3                                                                           CH.sub.3                                                                          H   H   4-n-C.sub.3 H.sub.7                                                                 O                                                                                 ##STR36##                                                                          CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                     CO           C.sub.2 H.sub.5                                                                    1-cyclopropyl-α,.alph                                                    a.- diethyl-3,3-dimethyl-                                                      5-propyl//butyric acid          58 H   H  H   H   7-C.sub.2 H.sub.5                                                                   O C.sub.2 H.sub.5                                                                     CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                            C.sub.2 H.sub.5                                                                    1,8-diethyl-α-methyl/                                                    /                                                                              butyric acid                    59 CH.sub.3                                                                           CH.sub.3                                                                          CH.sub.3                                                                           H   5-F  O n-C.sub.4 H.sub.9                                                                   [CH(CH.sub.3)].sub.3 CO                                                                     C.sub.2 H.sub.5                                                                    1-butyl-6-fluoro-α,.b                                                    eta.-                                                                          γ,3,3,4-hexamethyl//                                                     butyric acid                    60 CH.sub.3                                                                           CH.sub.3                                                                          H   H   4-CH.sub.3                                                                          O n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)CH.sub.2 CH(C.sub.2                                         H.sub.5)CO   C.sub.2 H.sub.5                                                                    α,γ-diethyl-1-p                                                    ropyl-                                                                         3,3,5-trimethyl//                                                              butyric acid                    61 C.sub.2 H.sub.5                                                                    H  H   H   6-NO.sub.2                                                                          O n-C.sub.4 H.sub.9                                                                   [C(CH.sub.3).sub.2 ].sub.3 CO                                                               C.sub.2 H.sub.5                                                                    1-butyl-3-ethyl-7-                                                             nitro-α,β,.gamma                                                    .-                                                                             trimethyl//butyric                                                             acid                            62 CH.sub.3                                                                           CH.sub.3                                                                          H   H   4-n-C.sub.3 H.sub.7                                                                 O n-C.sub.3 H.sub.7                                                                   CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                                        C.sub.2 H.sub.5                                                                    α,β-diethyl-3,3-                                                    dimethyl-1,5-dipropyl//                                                        butyric acid                    63 H   H  H   H   7-OH O C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3).sub.2                                    CO          C.sub.2 H.sub.5                                                                    1-ethyl-8-hydroxy-                                                             α,α,γ,.ga                                                    mma.-tetramethyl//                                                             butyric acid                    64 CH.sub.3                                                                           H  CH.sub.3                                                                           H   4-OC.sub.2 H.sub.5                                                                  O C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2 ].sub.3 CO                                                               C.sub.2 H.sub.5                                                                    5-ethoxy-1-ethyl-α,.a                                                    lpha.,-                                                                        β,β,γ,.gamm                                                    a.,3,4-                                                                        octomethyl//butyric acid        64a                                                                               H   H  H   H   4-CH.sub.3                                                                          O CH.sub.3                                                                            CH.sub.2 CO  C.sub.2 H.sub.5                                                                    1,5-dimethyl//acetic                                                           acid, m.p. 150-152°                                                     C.                              64b                                                                               H   H  H   H   4-Cl O CH.sub.3                                                                            CH.sub.2 CO  CH.sub.3                                                                           5-chloro-1-methyl//                                                            acetic acid, m.p. 183-                                                         184° C.                  __________________________________________________________________________

                                      TABLE II                                     __________________________________________________________________________                                                      PRODUCT: [(PREFIX                                         KETOESTER OF         LISTED BELOW)-1,3,4,9-                                    FORMULA VI           TETRAHYDRO-                                                                    THIOPYRANO-                    EXAMPLE                                                                              STARTING MATERIAL OF FORMULA II                                                                      ##STR37##            [3,4-b]INDOLE-1-                                                              (SUFFIX LISTED BELOW)]        R.sup.2  R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                           R.sup.6                                                                              X R.sup.1                                                                             Alk.sup.1CO R.sup.19                                                                           PREFIX//SUFFIX                __________________________________________________________________________     65   H   H   H   H  H     S CH.sub.3                                                                            CO          C.sub.2 H.sub.5                                                                    1-methyl//carboxylic                                                           acid                          66   CH.sub.3                                                                           H   H   H  H     S C.sub.2 H.sub.5                                                                     CO          C.sub.2 H.sub.5                                                                    1-ethyl-3-methyl//                                                             carboxylic acid               67   i-C.sub.3 H.sub.7                                                                  H   H   H  5-CH.sub.3                                                                           S i-C.sub.3 H.sub.7                                                                   CO          CH.sub.3                                                                           1,3-diisopropyl-6-                                                             methyl//carboxylic                                                             acid                          68   CH.sub.3                                                                           CH.sub.3                                                                           H   H  5-OH  S CH.sub.3                                                                            CO          CH.sub.3                                                                           1,3,3-trimethyl-6-                                                             hydroxy-1-(1-propyl)//                                                         carboxylic acid               69   H   H   H   H  7-C.sub.2 H.sub.5                                                                    S n-C.sub.3 H.sub.7                                                                   CO          CH.sub.3                                                                           8-ethyl-1-propyl//                                                             carboxylic acid               70   H   H   i-C.sub.3 H.sub.7                                                                  H  H     S                                                                                 ##STR38##                                                                          CO          CH.sub.3                                                                           1-cyclopropyl-4-                                                               isopropyl//carboxylic                                                          acid                          71   CH.sub.3                                                                           CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   H     S                                                                                 ##STR39##                                                                          CO          CH.sub.3                                                                           1-cyclopentyl-4,4-                                                             diethyl-3,3-dimethyl//                                                         carboxylic acid               72   H   H   CH.sub.3                                                                           H  H     S CH.sub.3                                                                            CH.sub.2 CO C.sub.2 H.sub.5                                                                    1,4-dimethyl//acetic                                                           acid                          73   H   H   H   H  H     S C.sub.2 H.sub.5                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                    1-ethyl//acetic acid,                                                          m.p. 138° C.           74   H   H   H   H  H     S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    1-propyl//acetic acid,                                                         m.p. 127-129° C.       75   H   H   H   H  H     S i-C.sub.3 H.sub.7                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    1-isopropyl//acetic                                                            acid                          76   CH.sub.3                                                                           H   H   H  H     S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    3-methyl-1-propyl//                                                            acetic acid                   77   CH.sub.3                                                                           H   C.sub.2 H.sub.5                                                                    CH.sub.3                                                                          H     S C.sub.2 H.sub.5                                                                     CH.sub.2 CO C.sub.2 H.sub.5                                                                    1,4-diethyl-3-methyl//                                                         acetic acid                   78   H   H   H   H  H     S CH.sub.3                                                                            CH(CH.sub.3)CO                                                                             C.sub.2 H.sub.5                                                                    α,1-dimethyl//aceti                                                      c                                                                              acid                          79   H   H   H   H  H     S                                                                                 ##STR40##                                                                          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                    1-cyclohexyl-α,.alp                                                      ha.-  dimethyl//acetic                                                         acid                          80   H   H   H   H  H     S t-C.sub.4 H.sub.9                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    1-t-butyl//acetic acid        81   H   H   H   H  H     S n-C.sub.4 H.sub.9                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    1-butyl//acetic acid          82   H   H   H   H  7-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    8-methyl-1-propyl//                                                            acetic acid                   83   H   H   H   H  5-Br  S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    6-bromo-1-propyl//                                                             acetic acid                   84   H   H   H   H  5-OCH.sub.3                                                                          S CH.sub.3                                                                            CH.sub.2 CO CH.sub.3                                                                           6-methoxy-1-methyl//                                                           acetic acid                   85   H   H   H   H  5-OCOCH.sub.3                                                                        S CH.sub.3                                                                            CH.sub.2 CO C.sub.2 H.sub.5                                                                    6-acetoxy-1-methyl//                                                           acetic acid                   86   H   H   H   H  5-benzyl-                                                                            S CH.sub.3                                                                            CH.sub.2 CO C.sub.2 H.sub.5                                                                    6-benzyloxy-1-methyl//                            oxy                          acetic acid                   87   H   H   H   H  4-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    5-methyl-1-propyl//                                                            acetic acid                   88   H   H   H   H  6-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CO C.sub.2 H.sub.5                                                                    7-methyl-1-propyl//                                                            acetic acid                   89   H   H   H   H  7-F   S CH.sub.3                                                                            C(.sub.2 CH.sub.5).sub.2 CO                                                                C.sub.2 H.sub.5                                                                    α,α-diethyl-8                                                      -fluoro-1-                                                                     methyl//acetic acid           90   CH.sub.3                                                                           CH.sub.3                                                                           H   H  5-Cl  S n-C.sub.3 H.sub.7                                                                   CH(iC.sub.3 H.sub.7)CO                                                                     C.sub.2 H.sub.5                                                                    6-chloro-3,3-dimethyl-                                                         α-isopropyl-1-                                                           propyl//acetic acid           91   CH.sub.3                                                                           CH.sub.3                                                                           H   H  5-OC.sub.2 H.sub.5                                                                   S                                                                                 ##STR41##                                                                          CH(C.sub.2 H.sub.5)CO                                                                      C.sub.2 H.sub.5                                                                    1-cyclopropyl-α,.al                                                      pha.-  diethyl-3,3-                                                            dimethyl-6-ethoxy//                                                            acetic acid                   92   CH.sub.3                                                                           CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   6-C.sub.2 H.sub.5                                                                    S                                                                                 ##STR42##                                                                          C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                    1-cyclohexyl-α,.alp                                                      ha.,3,5-                                                                       tetramethyl-4,4,7-                                                             triethyl//acetic  acid        93   CH.sub.3                                                                           H   n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                 4-n-C.sub.3 H.sub.7                                                                  S C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CO                                                                             C.sub.2 H.sub.5                                                                    α,3-dimethyl-1-ethy                                                      l-                                                                             4,4,5-tripropyl//                                                              acetic acid                   94   H   H   H   H  H     S n-C.sub.3 H.sub.7                                                                   C(CH.sub.3).sub.2 CO                                                                       C.sub.2 H.sub.5                                                                    α,α-dimethyl-                                                      1-                                                                             propyl//acetic acid           95   C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   4-C.sub.2 H.sub.5                                                                    S t-C.sub.4 H.sub.9                                                                   C(i-C.sub.3 H.sub.7).sub.2 CO                                                              C.sub.2 H.sub.5                                                                    1-t-butyl-α,α                                                      -                                                                              diisopropyl-3,3,4,4,-                                                          5-pentaethyl//acetic                                                           acid                          96   H   H   H   H  H     S CH.sub.3                                                                            CH.sub.2 CH.sub.2 CO                                                                       C.sub.2 H.sub.5                                                                    1-methyl//                                                                     propionic acid                97   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           ##STR43##                                                                           S C.sub.2 H.sub.5                                                                     CH.sub.2 CH(CH.sub.3)CO                                                                    C.sub.2 H.sub.5                                                                    8-acetoxy-1-ethyl-                                                             α,3,3,4,4-                                                               pentamethyl//  propionic                                                       acid                          98   H   H   H   H  6-OH  S n-C.sub.3 H.sub.7                                                                   CH.sub.2 C(C.sub.2 H.sub.5).sub.2                                                          C.sub.2 H.sub.5                                                                    β,β-diethyl-7-                                                       hydroxy-1-propyl//                                                             propionic acid                99   CH.sub.3                                                                           H   H   H  7-NO.sub.2                                                                           S                                                                                 ##STR44##                                                                          CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                           C.sub.2 H.sub.5                                                                    1-cyclobutyl-3-                                                                methyl-8-nitro-α-                                                        ropyl//propionic  acid        100  H   H   CH.sub.3                                                                           H  5-CH.sub.3                                                                           S                                                                                 ##STR45##                                                                          C(CH.sub.3).sub.2 C(CH.sub.3).sub.2                                                        C.sub.2 H.sub.5                                                                    1-cyclopropyl-α,.al                                                      pha.,β,β,                                                            4,6-hexamethyl//                                                               propionic acid                101  CH.sub.3                                                                           H   H   H  H     S CH.sub.3                                                                            CH.sub.2 C(n-C.sub.3 H.sub.7).sub.2                                                        C.sub.2 H.sub.5                                                                    1,3-dimethyl-α,.alp                                                      ha.-                                                                           dipropyl//propionic                                                            acid                          102  CH.sub.3                                                                           H   C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   H     S C.sub.2 H.sub.5                                                                     CH(CH.sub.3)C(CH.sub.3).sub.2 CO                                                           CH.sub.3                                                                           1,4,4-triethyl-α,.a                                                      lpha.,β,-                                                                 3-tetramethyl//                                                                propionic acid                103  H   H   CH.sub.3                                                                           CH.sub.3                                                                          H     S C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 CO                                                              CH.sub.3                                                                           1-ethyl-β,β,4,4                                                      -                                                                              tetramethyl//                                                                  propionic acid                104  H   H   n-C.sub.3 H.sub.7                                                                  H                                                                                  ##STR46##                                                                           S                                                                                 ##STR47##                                                                          C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                             H.sub.5)CO  CH.sub.3                                                                           1-cyclopentyl-5-                                                               propionoxy-4-propyl-                                                           α,β,β-tri                                                      ethyl//   propionic                                                            acid                          105  n-C.sub.3 H.sub.7                                                                  H   H   H  4-OCH.sub.3                                                                          S n-C.sub.3 H.sub.7                                                                   CH.sub.2 CH(CH.sub.3)CO                                                                    C.sub.2 H.sub.5                                                                    1,3-dipropyl-5-                                                                methoxy-α-methyl//                                                       propionic acid                106  C.sub.2 H.sub.5                                                                    H   H   H  5-NO.sub.2                                                                           S CH.sub.3                                                                            C(C.sub.2 H.sub.5).sub.2 C(C.sub.2                                             H.sub.5).sub.2 CO                                                                          C.sub.2 H.sub.5                                                                    1-methyl-6-nitro-                                                              α,α,β,.b                                                      eta.,3-pentaethyl//                                                            propionic acid                107  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H   H  4-C.sub.2 H.sub.5                                                                    S n-C.sub.3 H.sub.7                                                                   CH(n-C.sub.3 H.sub.7)CH.sub.2 CO                                                           CH.sub.3                                                                           β,1-dipropyl-3,3,5-                                                       triethyl//propionic                                                            acid                          108  H   H   H   H  6-OC.sub.2 H.sub.5                                                                   S                                                                                 ##STR48##                                                                          CH(C.sub.2 H.sub.5)CH(C.sub.2 H.sub.5)CO                                                   C.sub.2 H.sub.5                                                                    1-cyclopropyl-α,.be                                                      ta.-  diethyl-7-ethoxy//                                                        propionic acid               109  H   H   H   H  H     S CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 CO                                                              C.sub.2 H.sub.5                                                                    1-methyl//butyric acid        110  CH.sub.3                                                                           H   H   H  H     S C.sub.2 H.sub.5                                                                     CH(CH.sub.3)CH.sub.2 CH.sub.2 CO                                                           C.sub.2 H.sub.5                                                                    γ,3-dimethyl-1-ethy                                                      l//                                                                            butyric acid                  111  CH.sub.3                                                                           CH.sub.3                                                                           H   H  H     S n-C.sub.3 H.sub.7                                                                   C(C.sub.2 H.sub.5).sub.2 CH.sub.2                                              CH.sub.2 CO C.sub.2 H.sub.5                                                                    γ,γ-diethyl-3                                                      ,3-                                                                            dimethyl-1-propyl//                                                            butyric acid                  112  CH.sub.3                                                                           CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                  H  H     S                                                                                 ##STR49##                                                                          C(n-C.sub.3 H.sub.7).sub.2 CH(n-C.sub.3                                        H.sub.7 CH.sub.2 CO                                                                        C.sub.2 H.sub.5                                                                    1-cyclobutyl-3,3-                                                              dimethyl-β,γ,.                                                      gamma.,4-  tetrapropyl//                                                        butyric acid                 113  H   H   C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   6-Cl  S CH.sub.3                                                                            [C(C.sub.2 H.sub.5).sub.2 9.sub.2                                              CH(C.sub.2 H.sub.5)CO                                                                      C.sub.2 H.sub.5                                                                    7-chloro-α                                                               ,β,β,γ,.g                                                      amma.-                                                                         4,4-heptaethyl-1-                                                              methyl//butyric acid          114  H   H   CH.sub.3                                                                           H  4-CH.sub.3                                                                           S C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2] 3 CO                                                                   C.sub.2 H.sub.5                                                                    1-ethyl-α,α,.                                                      beta.,β,γ,.gam                                                      ma.-                                                                           4,5-octamethyl//                                                               butyric acid                  115  C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H                                                                                  ##STR50##                                                                           S n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)[C(C.sub.2 H.sub.5)].s                                      ub.2 CO     C.sub.2 H.sub.5                                                                    6-acetoxy-α,α                                                      ,β,β-                                                                γ,3,3,4-octaethyl-1                                                      -  propyl//butyric acid       116  H   H   CH.sub.3                                                                           CH.sub.3                                                                          7-OCH.sub.3                                                                          S                                                                                 ##STR51##                                                                          CH.sub.2 [C(CH.sub.3).sub.3]                                                               C.sub.2 H.sub.5                                                                    1-cyclobutyl-α,.alp                                                      ha.,β,-                                                                   β,4,4-hexamethyl-8-n                                                        methoxy//butyric acid       117  H   H   H   H  4-Br  S                                                                                 ##STR52##                                                                          CH.sub.2 CH(CH.sub.3)C(CH.sub.3).sub.2                                         CO          C.sub.2 H.sub.5                                                                    5-bromo-1-cyclopentyl                                                          α,α,β-tr                                                      imethyl//  butyric acid       118  CH.sub.3                                                                           CH.sub.3                                                                           H   H  4-n-C.sub.3 H.sub.7                                                                  S                                                                                 ##STR53##                                                                          CH.sub.2 CH.sub.2 C(C.sub.2 H.sub.5).sub.                                      2 CO        C.sub.2 H.sub.5                                                                    1-cyclopropyl-α,.al                                                      pha.-                                                                          diethyl-3,3-dimethyl                                                           5-propyl//butyric  acid       119  H   H   H   H  7-C.sub.2 H.sub.5                                                                    S C.sub.2 H.sub.5                                                                     CH.sub.2 CH.sub.2 CH(CH.sub.3)CO                                                           C.sub.2 H.sub.5                                                                    1,8-diethyl-α-                                                           methyl//butyric acid          120  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           H  5-F   S n-C.sub.4 H.sub.9                                                                   [CH(CH.sub.3)].sub.3 CO                                                                    C.sub.2 H.sub.5                                                                    1-butyl-6-fluoro-                                                              α,β,γ,3,                                                      3,4-                                                                           hexamethyl//butyric                                                            acid                          121  CH.sub.3                                                                           CH.sub.3                                                                           H   H  4-CH.sub.3                                                                           S n-C.sub.3 H.sub.7                                                                   CH(C.sub.2 H.sub.5)CH.sub.2 CH(C.sub.2                                         H.sub.5)CO  C.sub.2 H.sub.5                                                                    α,γ-diethyl-1                                                      -                                                                              propyl-3,3,5-trimethyl-                                                        butyric acid                  122  C.sub.2 H.sub.5                                                                    H   H   H  6-NO.sub.2                                                                           S n-C.sub.4 H.sub. 9                                                                  [C(CH.sub.3).sub.2]3 CO                                                                    C.sub.2 H.sub.5                                                                    1-butyl-3-ethyl-7-                                                             nitro-α,β,.gam                                                      ma.-                                                                           trimethyl//butyric                                                             acid                          123  CH.sub.3                                                                           CH.sub.3                                                                           H   H  4-n-C.sub.3 H.sub.7                                                                  S n-C.sub.3 H.sub.7                                                                   CH.sub.2 [CH(C.sub.2 H.sub.5)].sub.2                                                       C.sub.2 H.sub.5                                                                    α,β-diethyl-                                                        3,3-dimethyl-1,5-                                                              dipropyl//butyric                                                              acid                          124  H   H   H   H  7-OH  S C.sub.2 H.sub.5                                                                     C(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3).su                                      b.2 CO      C.sub.2 H.sub.5                                                                    1-ethyl-8-hydroxy-                                                             α,α,γ,.                                                      gamma.-tetramethyl//                                                           butyric acid                  125  CH.sub.3                                                                           H   CH.sub.3                                                                           H  4-OC.sub.2 H.sub.5                                                                   S C.sub.2 H.sub.5                                                                     [C(CH.sub.3).sub.2] 3 CO                                                                   C.sub.2 H.sub.5                                                                    5-ethoxy-1-ethyl-                                                              α,α,β,.b                                                      eta.,γ,γ,3,4-                                                      octomethyl//butyric                                                            acid                          __________________________________________________________________________

EXAMPLE 126 N,N,1-TRIMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETAMIDE[VII: R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O AND Z = CH₂ CON(CH₃)₂ ]

To a stirred solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g. 0.061 mole), prepared as described in Example 1, in dry tetrahydrofuran (300 ml), cooled to -5° C., is added triethylamine (18.5 g, 0.183 mole), followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture is stirred at -5° C. for 2 hr. This mixture, which now contains the mixed anhydride of the above starting material, is added dropwise to a cooled 40% aqueous solution of the amine, dimethylamine (225 ml). The resulting mixture is stirred at room temperature for one-half hour. Most of the tetrahydrofuran is evaporated, and the residue partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography on silica gel. Elution with 20% ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate affords the title compound, m.p. 149°-151° C., γ_(max) ^(CHCl).sbsb.3 3375, 1634 cm⁻ ¹.

In the same manner but replacing the 40% aqueous solution of dimethylamine with an equivalent amount of ammonium hydroxide (concentrated), methylamine (30% aqueous solution), n-hexylamine (20% aqueous solution), diethylamine (30% aqueous solution), isopropylamine (40% aqueous solution), ethylamine (70% aqueous solution), pyrrolidine (50% aqueous solution), piperidine, morpholine, N-methylpiperazine,

1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 158°-160° C.,

N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 138°-140° C.,

N-hexyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,N-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 99° C., ν_(max) ^(CHCl).sbsb.3 3350, 1620 cm⁻ ¹,

N-isopropyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 151°-153° C.,

N-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, m.p. 152°-153° C.,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]pyrrolidine, m.p. 119°-120° C.,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolo-1-yl)acetyl]piperidine, m.p. 148°-149° C.,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]morpholine, m.p. 141°-142° C., and

1-methyl-4-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)-acetyl]piperazine, are obtained respectively.

By following the procedure of Example 126 but using as starting material an equivalent amount of one of the acid compounds of formula VII, described in Examples 2 to 125, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine described in Example 126, then the corresponding amide compound of formula VII is obtained. Examples of such amides are listed as products in Tables III, IV, V and VI together with the appropriate starting material and amine used for the preparation of the amide. In each case the starting material is noted by the example in which it is prepared.

                                      TABLE III                                    __________________________________________________________________________           NO. OF THE EXAMPLE  PRODUCT: [(PREFIX LISTED BELOW)-                           IN WHICH STARTING   1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                           MATERIAL IS         INDOLE-1-(SUFFIX LISTED BELOW)]                      EXAMPLE                                                                              PREPARED     AMINE  PREFIX//SUFFIX                                       __________________________________________________________________________     127   2            CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//propionamide,                                                    m.p. 149 - 150° C.                            128   2            NH.sub.3                                                                              1-methyl//propionamide                               129   2            (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//propionamide                        130   2            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//propionamide                       131   2            (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-methyl//propionamide                   132   4            CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//carboxamide                            133   4            NH.sub.3                                                                              1-methyl//carboxamide, m.p. 188 -                                              189° C.                                       134   4            (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//carboxamide                         135   4            n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//carboxamide                        136   4            C.sub.2 H.sub.5 NH.sub.2                                                              N-ethyl-1-methyl//carboxamide                        137   5            CH.sub.3 NH.sub.2                                                                     N,3-dimethyl-1-ethyl//carboxamide                    138   9            (CH.sub.3).sub.2 NH                                                                   1-cyclopropyl-N,N-dimethyl-4-iso-                                              propyl//carboxamide                                  139   11           (CH.sub.3).sub.2 NH                                                                   N,N,1,4-tetramethyl//acetamide                       140   12           CH.sub.3 NH.sub.2                                                                     1-ethyl-N-methyl//acetamide                          141   12           NH.sub.3                                                                              1-ethyl//acetamide                                   142   12           (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-1-ethyl//acetamide                      143   12           n-C.sub.16 H.sub.13 NH.sub.2                                                          1-ethyl-N-hexyl//acetamide                           144   12           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N,1-triethyl//acetamide                            145   13           CH.sub.3 NH.sub.2                                                                     N-methyl-1-propyl//acetamide                         146   13           NH.sub.3                                                                              1-propyl//acetamide                                  147   13           (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-1-propyl//acetamide,                                              m.p. 159 - 162° C.                            148   13           n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-propyl//acetamide                          149   13           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-propyl//acetamide                      150   14           CH.sub.3 NH.sub.2                                                                     1-isopropyl-N-methyl//acetamide                      151   14           NH.sub.3                                                                              1-isopropyl//acetamide                               152   14           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1-isopropyl//acetamide                   153   15           CH.sub.3 NH.sub.2                                                                     N,3-dimethyl-1-propyl//acetamide                     154   15           (CH.sub.3).sub.2 NH                                                                   1-propyl-N,N,3-trimethyl//                                                     acetamide                                            155   15           n-C.sub.6 H.sub.13 NH.sub.2                                                           n-hexyl-3-methyl-1-propyl//                                                    acetamide                                            156   15           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-3-methyl-1-propyl//                                                acetamide                                            157   17           CH.sub.3 NH.sub.2                                                                     N,α,1-trimethyl//acetamide                     158   17           NH.sub.3                                                                              α,1-dimethyl//acetamide                        159   17           (CH.sub.3).sub.2 NH                                                                   N,N,α,1-tetramethyl//acetamide                 160   17           n-C.sub.6 H.sub.13 NH.sub.2                                                           α,1-dimethyl-N-hexyl//acetamide                161   17           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-α,1-dimethyl//                                               acetamide                                            162   18           CH.sub.3 NH.sub.2                                                                     1-cyclohexyl-N,α,α-trimethyl//                                     acetamide                                            163   21           CH.sub.3 NH.sub.2                                                                     N,8-dimethyl-1-propyl//acetamide                     164   25           NH.sub.2                                                                              6-benzyloxy-1-methyl//acetamide                      165   26           (CH.sub.3).sub.2 NH                                                                   1-propyl-N,N,5-trimethyl//                                                     acetamide                                            166   30           n-C.sub.6 H.sub.13 NH.sub.2                                                           1-cyclopropyl-α,α-diethyl-3,3-                                     dimethyl-6-ethoxy-N-hexyl//                                                    acetamide                                            167   35           CH.sub.3 NH.sub.2                                                                     5-iodo-1-isopropyl-N-methyl//                                                  propionamide                                         168   38           NH.sub.2                                                                              1-cyclobutyl-3-methyl-8-nitro-                                                 α-propyl//propionamide                         169   41           (CH.sub.3).sub.2 NH                                                                   N,N,α,α,β,3-hexamethyl-1,4,4-                                 triethyl//propionamide                               170   44           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1,3-dipropyl-5-                                                    methoxy-α-methyl//propionamide                 171   46           CH.sub.3 NH.sub.2                                                                     N-methyl-β,1-dipropyl-3,3,5-                                              triethyl//propionamide                               172   48           (CH.sub.3).sub.2 NH                                                                   N,N,1-trimethyl//butyramide                          173   48           CH.sub.3 NH.sub.2                                                                     N,1-dimethyl//butyramide                             174   48           NH.sub.2                                                                              1-methyl//butyramide                                 175   48           n-C.sub.6 H.sub.13 NH.sub.2                                                           N-hexyl-1-methyl//butyramide                         176   51           CH.sub.3 NH.sub.2                                                                     1-cyclobutyl-β,γ,γ,4-tetrapropy                               l-                                                                             N,3,3-trimethyl//butyramide                          177   53           (CH.sub.3).sub.2 NH                                                                   N,N,α,α,α,β,β,.gamma                               .,γ,4,5-decamethyl-                                                      1-ethyl//butyramide                                  178   56           NH.sub.2                                                                              5-bromo-1-cyclopentyl-α,α,β-                                  trimethyl//butyramide                                179   58           CH.sub.3 NH.sub.2                                                                     1,8-diethyl-N,α-dimethyl//                                               butyramide                                           180   60           (C.sub.2 H.sub.5).sub.2 NH                                                            1-propyl-N,N,α,γ-tetraethyl-                                       3,3,5-trimethyl//butyramide                          181   62           n-C.sub.6 H.sub.13 NH.sub.2                                                           α,β-diethyl-3,3-dimethyl-                                           1,5-dipropyl-N-hexyl//butyramide                     __________________________________________________________________________

                                      TABLE IV                                     __________________________________________________________________________           NO. OF THE EXAMPLE    PRODUCT: [(PREFIX LISTED BELOW)-                         IN WHICH STARTING     1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                         MATERIAL IS           INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                              PREPARED      AMINE      PREFIX//SUFFIX                                  __________________________________________________________________________     182   2            pyrrolidine                                                                             1-[(1-methyl//propionyl]pyrrolidine                183   2            piperidine                                                                              1-[(1-methyl//propionyl]piperidine                 184   2            morpholine                                                                              4- (1-methyl//propionyl]morpholine                 185   2            piperazine                                                                              1-[(1-methyl//propionyl]piperazine                 186   2            N-methyl-                                                                               1-methyl-4-[1-methyl//propionyl]-                                     piperazine                                                                              piperazine                                         187   2            N-piperazine-                                                                           1-(2-hydroxyethyl)-4-[(1-methyl//                                     ethanol  propionyl]piperazine                               188   4            pyrrolidine                                                                             1-[(1-methyl//carbonyl]pyrrolidine                 189   4            morpholine                                                                              4-[(1-methyl//carbonyl]morpholine                  190   5            N-ethyl- 1-ethyl-4-[(1-ethyl-3-methyl//                                        piperazine                                                                              carbonyl]piperazine                                191   11           piperidine                                                                              1-[(1,4-dimethyl//acetyl]-                                                     piperidine                                         192   12           morpholine                                                                              4-[(1-ethyl//acetyl]morpholine                     193   12           N-piperazine-                                                                           1-(3-hydroxypropyl)-4-                                                propanol [(1-ethyl//acetyl]piperazine                       194   13           pyrrolidine                                                                             1-[(1-propyl//acetyl]pyrrolidine                   195   13           morpholine                                                                              4-[(1-propyl//acetyl]morpholine                    196   14           piperidine                                                                              1-[(1-isopropyl//acetyl]piperidine                 197   15           piperazine                                                                              1-[(3-methyl-1-propyl//acetyl]-                                                piperazine                                         198   17           N-ethyl- 1-ethyl-4-[(α,1-dimethyl//acetyl]-                              piperazine                                                                              piperazine                                         199   25           pyrrolidine                                                                             1-[(6-benzyloxyl-1-methyl//acetyl]-                                            pyrrolidine                                        200   26           piperidine                                                                              1-[(5-methyl-1-propyl//acetyl]                                                 piperidine                                         201   30           morpholine                                                                              4-[(1-cyclopropyl-α,α-diethyl-                                     3,3-dimethyl-6-ethoxy//acetyl]-                                                morpholine                                         202   36           piperazine                                                                              1-[8-acetoxy-1-ethyl-α,3,3,4,4-                                          pentamethyl//propionyl]piperazine                  203   39           N-piperazine-                                                                           1-(2-hydroxyethyl)-4-[(1-cyclo-                                       ethanol  propyl-α,α,β,β,4,6-hexam                                 ethyl//                                                                        propionyl]piperazine                               204   40           pyrrolidine                                                                             1-[(1,3-dimethyl-α,α-dipropyl//                                    propionyl]pyrrolidine                              205   42           morpholine                                                                              4-[(1-ethyl-β,β,4,4-tetramethyl//                                    propionyl]morpholine                               206   47           N-propyl-                                                                               1-propyl-4-[(1-cyclopropyl-α,β-                            piperazine                                                                              diethyl-6-ethoxy//propionyl]-                                                  piperazine                                         207   48           pyrrolidine                                                                             1-[(1-methyl//butyryl]pyrrolidine                   207a 48           N-piperazine-                                                                           1-(hydroxymethyl)-4-[(1-methyl//                                      methanol butyryl]piperazine                                 208   50           piperidine                                                                              1-[γ,γ-diethyl-3,3-dimethyl-1-                                     propyl//butyryl]piperidine                         209   52           morpholine                                                                              4-[(7-chloro-α,β,β,γ,.ga                                 mma.,4,4-                                                                      heptaethyl-1-methyl//butyryl]-                                                 morpholine                                         210   59           piperazine                                                                              1-[(1-butyl-6-fluoro-α,β,γ,3,                                 3,4-                                                                           hexamethyl//butyryl]piperazine                     __________________________________________________________________________

                                      TABLE V                                      __________________________________________________________________________                                 PRODUCT:                                                 NO. OF THE EXAMPLE    [(PREFIX LISTED BELOW)-1,3,4,9-                          IN WHICH STARTING     TETRAHYDROTHIOPYRANO-[3,4-b]-                            MATERIAL IS           INDOLE-1-(SUFFIX LISTED BELOW)]                    EXAMPLE                                                                              PREPARED      AMINE      PREFIX//SUFFIX                                  __________________________________________________________________________     211   3            CH.sub.3 NH.sub.2                                                                       N,1-dimethyl//acetamide                            212   3            NH.sub.2 1-methyl//acetamide                                213   3            n-C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//acetamide                        214   3            (CH.sub.3).sub.2 NH                                                                     N,N,1-trimethyl//acetamide,                                                    m.p. 182° C.                                215   3            (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-1-methyl//acetamide                    216   96           CH.sub.3 NH.sub.2                                                                       N,1-dimethyl//propionamide                         217   96           NH.sub.3 1-methyl//propionamide                             218   96           (CH.sub.3).sub.2 NH                                                                     N,N,1-trimethyl//propionamide                      219   96           n-C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//propionamide                     220   96           (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-1-methyl//propion-                                                 amide                                              221   65           CH.sub.3 NH.sub.2                                                                       N,1-dimethyl//carboxamide                          222   65           NH.sub.3 1-methyl//carboxamide                              223   65           (CH.sub.3).sub.2 NH                                                                     N,N,1-trimethyl//carboxamide                       224   65           n-C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//carboxamide                      225   65           (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-1-methyl//carboxamide                  226   66           CH.sub.3 NH.sub.2                                                                       N,3-dimethyl-1-ethyl//carboxamide                  227   69           NH.sub.3 8-ethyl-1-propyl//carboxamide                      228   70           (CH.sub.3).sub.2 NH                                                                     1-cyclopropyl-N,N-dimethyl-4-                                                  isopropyl//carboxamide                             229   72           (CH.sub.3).sub.2 NH                                                                     N,N,1,4-tetramethyl//acetamide                     230   73           CH.sub.3 NH.sub.2                                                                       1-ethyl-N-methyl//acetamide                        231   73           NH.sub.3 1-ethyl//acetamide                                 232   73           (CH.sub.3).sub.2 NH                                                                     N,N-dimethyl-1-ethyl//acetamide                    233   73           n-C.sub.16 H.sub.13 NH.sub.2                                                            1-ethyl-N-hexyl//acetamide                         234   73           (C.sub.2 H.sub.5).sub.2 NH                                                              N,N,1-triethyl//acetamide                          235   74           CH.sub.3 NH.sub.2                                                                       N-methyl-1-propyl//acetamide                       236   74           NH.sub.3 1-propyl//acetamide                                237   74           (CH.sub.3).sub.2 NH                                                                     N,N-dimethyl-1-propyl//acetamide                   238   74           n-C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-propyl//acetamide                        239   74           (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-1-propyl//acetamide                    240   75           CH.sub.3 NH.sub.2                                                                       1-isopropyl-N-methyl//acetamide                    241   75           NH.sub.3 1-isopropyl//acetamide                             242   75           (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-1-isopropyl//acetamide                 243   76           CH.sub.3 NH.sub.2                                                                       N,3-dimethyl-1-propyl//acetamide                   244   76           NH.sub.3 3-methyl-1-propyl//acetamide                       245   76           (CH.sub.3).sub.2 NH                                                                     1-propyl-N,N,3-trimethyl//                                                     acetamide                                          246   76           n-C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-3-methyl-1-propyl//                                                    acetamide                                          247   76           (C.sub.2 H.sub.5).sub.2 NH                                                              N,N,diethyl-3-methyl-1-propyl//                                                acetamide                                          248   78           CH.sub.3 NH.sub.2                                                                       N,α,1-trimethyl//acetamide                   249   78           NH.sub.3 α,1-dimethyl//acetamide                      250   78           (CH.sub.3).sub.2 NH                                                                     N,N,α,1-tetramethyl//acetamide               251   78           n-C.sub.6 H.sub.13 NH.sub.2                                                             α,1-dimethyl-N-hexyl//acetamide              252   78           (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-dimethyl-α,1-dimethyl//                                              acetamide                                          253   79           CH.sub.3 NH.sub.2                                                                       1-cyclohexyl-N,α,α-trimethyl//                                     acetamide                                          254   82           CH.sub.3 NH.sub.2                                                                       N,8-dimethyl-1-propyl//acetamide                   255   83           NH.sub.2 6-bromo-1-propyl//acetamide                        256   89           (CH.sub.3).sub.2 NH                                                                     α,α-diethyl-8-fluoro-N,N,1-                                        trimethyl//acetamide                               257   91           n-C.sub.6 H.sub.13 NH.sub.2                                                             1-cyclopropyl-α,α-diethyl-3,3-                                     dimethyl-6-ethoxy-N-hexyl//                                                    acetamide                                          258   99           NH.sub.2 1-cyclobutyl-3-methyl-8-nitro-                                                 α-propyl//propionamide                       259   102          (CH.sub.3).sub.2 NH                                                                     N,N,α,α,β,3-hexamethyl-1,4,4-                                 N                                                                              triethyl//propionamide                             260   105          (C.sub.2 H.sub.5).sub.2 NH                                                              N,N-diethyl-1,3-dipropyl-5-                                                    methoxy-α-methyl//propionamide               261   107          CH.sub.3 NH.sub.2                                                                       β,1-dipropyl-N-methyl-3,3,5-                                              triethyl//propionamide                             262   108          CH.sub.3 NH.sub.2                                                                       1-cyclopropyl-α,β-diethyl-6-                                        ethoxy-N-methyl//propionamide                      263   109          (CH.sub.3).sub.2 NH                                                                     N,N,1-trimethyl//butyramide                        264   109          CH.sub.3 NH.sub.2                                                                       N,1-dimethyl//butyramide                           265   109          n-C.sub.6 H.sub.13 NH.sub.2                                                             N-hexyl-1-methyl//butyramide                       266   112          CH.sub.3 NH.sub.2                                                                       1-cyclobutyl-β,γ,γ,4-tetrapro                                 pyl-                                                                           N,3,3-trimethyl//butyramide                        267   113          (CH.sub.3).sub.2 NH                                                                     7-chloro-α,β,β,γ,γ                                 ,4,4-heptaethyl-                                                               N,N,1-trimethyl//butyramide                        268   117          NH.sub.2 5-bromo-1-cyclopentyl-α,α,β-                                  trimethyl//butyramide                              269   119          CH.sub.3 NH.sub.2                                                                       1,8-diethyl-N,α-dimethyl//                                               butyramide                                         270   121          (C.sub.2 H.sub.5).sub.2 NH                                                              1-propyl-N,N,α,γ-tetraethyl-                                       3,3,5-trimethyl//butyramide                        271   123          n-C.sub.6 H.sub.13 NH.sub.2                                                             α,β-diethyl-3,3-dimethyl-1,5-                                       dipropyl-N-hexyl//butyramide                       __________________________________________________________________________

                                      TABLE VI                                     __________________________________________________________________________                               PRODUCT: [(PREFIX LISTED BELOW)-                     NO. OF THE EXAMPLE        1,3,4,9-TETRAHYDROTHIOPYRANO-                        IN WHICH STARTING         [3,4-b]INDOLE-1-(SUFFIX LISTED                       MATERIAL IS               BELOW)]                                              EXAMPLE                                                                             PREPARED      AMINE    PREFIX//SUFFIX                                     __________________________________________________________________________     272  3            pyrrolidine                                                                            1-[(1-methyl//acetyl]pyrrolidine                     273  3            piperidine                                                                             1-[(1-methyl//acetyl]piperidine                      274  3            morpholine                                                                             4-[(1-methyl//acetyl]morpholine                      275  3            piperazine                                                                             1-[(1-methyl//acetyl]piperazine                      276  3            N-methyl-                                                                              1-methyl-4-[1-methyl//acetyl]-                                         piperazine                                                                             piperazine                                           277  3            N-piperazine-                                                                          1-(2-hydroxyethyl)-4-[(1-methyl//                                      ethanol acetyl]piperazine                                    278  96           pyrrolidine                                                                            1-[(1-methyl//propionyl]-                                                      pyrrolidine                                          279  96           piperidine                                                                             1-[(1-methyl//propionyl]piperidine                   280  96           morpholine                                                                             4-[(1-methyl//propionyl]morpholine                   281  96           piperazine                                                                             1-[(1-methyl//propionyl]piperazine                   282  96           N-methyl-                                                                              1-methyl-4-[1-methyl//propionyl]-                                      piperazine                                                                             piperazine                                           283  96           N-piperazine-                                                                          1-(2-hydroxyethyl)-4-[(1-methyl//                                      ethaol  propionyl]piperazine                                 284  65           pyrrolidine                                                                            1-[(1-methyl//carbonyl]pyrrolidine                   285  65           morpholine                                                                             4-[(1-methyl//carbonyl]morpholine                    286  66           N-ethyl-                                                                               1-ethyl-4-[(1-ethyl-3-methyl//                                         piperazine                                                                             carbonyl]piperzine                                   287  72           piperidine                                                                             1-[(1,4-dimethyl//acetyl]-                                                     piperidine                                           288  73           morpholine                                                                             4-[(1-ethyl//acetyl]morpholine                       289  73           N-piperazine-                                                                          1-(3-hydroxypropyl)-4-[(1-ethyl//                                      propanol                                                                               acetyl]piperazine                                    290  74           pyrrolidine                                                                            1-[(1-propyl//acetyl]pyrrolidine                     291  74           morpholine                                                                             4-[(1-propyl//acetyl]morpholine                      292  75           piperidine                                                                             1-[(1-isopropyl//acetyl]piperidine                   293  76           piperazine                                                                             1-[(3-methyl-1-propyl//acetyl]-                                                piperazine                                           294  78           N-ethyl-                                                                               1-ethyl-4-[(α,1-dimethyl//acetyl]-                               piperazine                                                                             piperazine                                           295  78           N-methyl-                                                                              1-methyl-4-[(α,1-dimethyl//acetyl]-                              piperazine                                                                             piperazine                                           296  86           pyrrolidine                                                                            1-[(6-benzyloxyl-1-methyl//                                                    acetyl]pyrrolidine                                   297  87           piperidine                                                                             1-[(5-methyl-1-propyl//acetyl]-                                                Piperidine                                           298  91           morpholine                                                                             4-[(1-cyclopropyl-α,α-diethyl-                                     3,3-dimethyl-6-ethoxy//acetyl]-                                                morpholine                                           299  97           piperazine                                                                             1-](8-acetoxy-1-ethyl-α,3,3,4,4-                                         pentamethyl//propionyl]piperazine                    300  100          N-piperazine-                                                                          1-(2-hydroxyethyl)-4-[(1-cyclo-                                        ethanol propyl-α,α,β,β,4,6-hexamet                               hyl//                                                                          propionyl]piperazine                                 301  101          pyrrolidine                                                                            1-](1,3-dimethyl-α,α-dipropyl//                                    propionyl]pyrrolidine                                302  103          morpholine                                                                             4-[(1-ethyl-β,β,4,4-tetramethyl//                                    propionyl]morpholine                                 303  108          N-propyl-                                                                              1-propyl-4-[(1-cyclopropyl-α,β-                             piperazine                                                                             diethyl-6-ethoxy//propionyl]-                                                  piperazine                                           304  109          pyrrolidine                                                                            1-[(1-methyl//butyryl]pyrriolidine                   305  109          N-piperazine-                                                                          1-(hydroxymethyl)-4-[(1-methyl//                                       methanol                                                                               butyryl]piperazine                                   306  111          piperidine                                                                             1-[(γ,γ,-diethyl-3,3-dimethyl-1-                                   propyl//butyryl]piperidine                           307  113          morpholine                                                                             4-[(7-chloro-α,β,β,γ,.gamm                               a.,4,4-                                                                        heptaethyl-1-methyl//butyryl]-                                                 morpholine                                           308  120          piperazine                                                                             1-[(1-butyl-6-fluoro-α,β,γ,3,3,                               4-                                                                             hexamethyl//butyryl]piperazine                       __________________________________________________________________________

EXAMPLE 309 1-[2-(DIMETHYLAMINO)ETHYL]-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE [I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = CH₂ CH₂ N(CH₃)₂ ]

A solution of N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (5.0 g, 0.018 mole), prepared as described in Example 126, is added dropwise to a cooled, well-stirred mixture of lithium aluminum hydride (1.4 g, 0.036 mole) in 200 ml of ether. Stirring is continued for one hour at room temperature, then the mixture is heated under reflux for 2 hr.

After cooling in an ice-water bath, 6.2 ml of water is added dropwise to destroy the excess hydride. Then 100 ml more of water is added and the ether phase decanted. The aqueous phase is extracted once with benzene. The combined organic phases are washed with water, dried over sodium sulfate, and evaporated to dryness to afford 5 g of oil which crystallized on standing. The crystallized product is recrystallized from ether to afford the pure title compound, m.p. 133°-135° C., nmr(CDCl₃) δ1.53 (s, 3H), 2.07 (2H), 9.74 (1H), 10.55 (6H).

The corresponding oxalic acid addition salt (oxalate), 1-[(2-dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole oxalate, has m.p. 181°-183° C. after crystallization from methanol-ether.

In the same manner but replacing lithium aluminum hydride with an equivalent amount of lithium aluminum hydride-aluminum chloride, aluminum hydride-aluminum chloride, diborane and sodium borohydride-aluminum chloride, the title compound is also obtained.

In the same manner but replacing N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide with an equivalent amount of the following amides described in Example 126,

1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, N,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, N-hexyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N,N-diethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N-isopropyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

N-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]-pyrrolidine

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]-piperidine,

1-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]-morpholine, and

1-methyl-4-[(1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)-acetyl]piperazine, then there are obtained,

1-(2-aminoethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 80°-84° C., γ_(max) ^(CHCl).sbsb.3 3455, 3280cm⁻ ¹,

1-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 160°-163° C., (m.p. of corresponding oxalic acid addition salt, 140°-144° C.),

1-[2-(hexylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,

1-[2-(diethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]ind9le, m.p. 74°-76° C, m.p. of corresponding maleic acid addition salt, 98°-100° C.,

1-[2-(isopropylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, 1-[2-(ethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,

1-methyl-1-[2-(1-pyrrolidinyl)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole,

nmr (CDCl₃) δ 1.62 (3H), 2.00 (m, 4H), 4.05 (m, 2H),

m.p. of corresponding maleic acid addition salt (maleate), 192°-193° C.,

1-methyl-1-(2-piperidinoethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 146°-148° C., m.p. of corresponding maleic acid addition salt, 147°-149° C.,

1-methyl-1-(2-morpholinoethyl)-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (DMSO-d₆) δ1.50 (3H), 6.07 (2H), 6.87 - 7.65 (m, 4H), 10.86 (1H), m.p. of corresponding maleic acid addition salt, 192°-193° C., and

1-methyl-1-[2-(4-methyl-1-piperazinyl)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (CDCl₃) δ1.47 (3H), 2.58 (3H), 3.87 (t, 2H), [m.p. of corresponding maleic acid addition salt (i.e. dimaleate), 208°-210° C.], respectively.

By following the procedure of Example 309 but using as starting material an equivalent amount of one of the amide compounds of formula VII, described in Examples 127 to 308 instead of N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-acetamide, then the corresponding compounds of formula I in which R⁷ is hydrogen are obtained. Examples of such compounds of formula I are listed as products in Tables VII and VIII together with the appropriate starting material, amides of formula VII. In each case the starting material is noted by the example in which it is prepared.

                                      TABLE VII                                    __________________________________________________________________________           NO. OF THE EXAMPLE                                                             IN WHICH STARTING                                                                            PRODUCT: (PREFIX LISTED BELOW)-                                  MATERIAL IS   1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                           EXAMPLE                                                                              PREPARED      INDOLE                                                     __________________________________________________________________________     310   127           1-methyl-1-[3-(methylamino)propyl],                                            nmr (CDCl.sub.3) δ1.48 (3H), 1.87 (4H),                                  2.47 (3H), corresponding oxalic                                                acid addition salt has m.p.                                                    110° C.                                             311   128           1-(3-aminopropyl)-1-methyl                                 312   129           1-methyl-1-[3-(dimethylamino)-                                                 propyl], m.p. 114 - 116° C.,                                            corresponding oxalic acid                                                      addition salt has m.p. 168 - 172° C.                313   130           1-[3-(hexylamino)propyl]-1-methyl                          314   131           1-[3-(diethylamino)propyl]-1-                                                  methyl                                                     315   132           1-methyl-1-[(methylamino)methyl]                           316   133           1-(aminomethyl)-1-methyl,                                                      γ.sub.max.sup.CHCl 3                                                     3465, 3400, 3180, 2930,                                                        corresponding hydrochloric acid                                                addition salt (hydrochloride)                                                  has m.p. 251 - 252° C.                              317   134           1-[(dimethylamino)methyl]-1-                                                   methyl                                                     318   135           1-[(hexylamino)methyl]-1-methyl                            319   136           1-[(ethylamino)methyl]-1-methyl,                                               nmr (DMSO-d.sub.6) δ1.18 (3H),                                           1.62 (3H), 2.80 (2H); correspond-                                              ing hydrochloride acid addition                                                salt has m.p. 245 - 243° C.                         320   137           1-ethyl-3-methyl-1-[(methylamino)-                                             methyl]                                                    321   138           1-cyclopropyl-1-[(dimethylamino)-                                              methyl]-4-isopropyl                                        322   139           1,4-dimethyl-1-[2-(dimethylamino)-                                             ethyl]                                                     323   140           1-ethyl-1-[2-(methylamino)ethyl]                           324   141           1-(2-aminoethyl)-1-ethyl                                   325   142           1-[2-(dimethylamino)ethyl]-1-                                                  ethyl                                                      326   143           1-ethyl-1-[2-(hexylamino)ethyl]                            327   144           1-[2-(diethylamino)ethyl]-1-ethyl                          328   145           1-[2-(methylamino)ethyl]-1-propyl                          329   146           1-(aminoethyl)-1-propyl                                    330   147           1-[2-(dimethylamino)ethyl]-1-                                                  propyl, nmr (CDCl.sub.3) 0.84 (t,3H),                                          1.21 (3, 6H), 2.79 (t, 5 = 5.5 cps,                                            2H) corresponding maleic acid                                                  addition salt has m.p. 152 - 154° C.)               331   148           1-[2-(hexylamino)ethyl]-1-propyl                           332   149           1-[2-(diethylamino)ethyl]-1-propyl                         333   150           1-isopropyl-1-[2-(methylamino)-                                                ethyl]                                                     334   151           1-(2-aminoethyl)-1-isopropyl                               335   152           1-[2-(diethylamino)ethyl]-1-                                                   isopropyl                                                  336   153           3-methyl-1-[2-(methylamino)ethyl]-                                             1-propyl                                                   337   154           1-[2-(dimethylamino)ethyl]-3-                                                  methyl-1-propyl                                            338   155           1-[2-(hexylamino)ethyl]-3-methyl-                                              1-propyl                                                   339   156           1-[2-(diethylamino)ethyl]-3-                                                   methyl-1-propyl                                            340   157           1-[1-methyl-2-(methylamino)ethyl]-                                             1-methyl                                                   341   158           1-(2-amino-1-methyl-ethyl)-1-                                                  methyl                                                     342   159           1-[2-(dimethylamino)-1-methyl-                                                 ethyl]-1-methyl                                            343   160           1-[2-(hexylamino)-1-methyl-ethyl]-                                             1-methyl                                                   344   161           1-[2-(dimethylamino)-1-methyl-ethyl]-                                          1-methyl                                                   345   162           1-cyclohexyl-1-[1,1-dimethyl-2-                                                (methylamino)ethyl]                                        346   163           8-methyl-1-[2-(methylamino)ethyl]-                                             1-propyl                                                   347   164           1-(2-aminoethyl)-6-benzyloxy-1-                                                methyl                                                     348   165           1-[2-(dimethylamino)ethyl]-5-                                                  methyl-1-propyl                                            349   166           1-cyclopropyl-1-[1,1-diethyl-2-                                                (hexylamino)ethyl]-3,3-dimethyl-                                               6-ethoxy                                                   350   167           5-iodo-1-isopropyl-1-[3-(methyl-                                               amino)propyl]                                              351   168           1-(3-amino-2-propyl-propyl)-1-                                                 cyclobutyl-3-methyl-8-nitro                                352   169           1-[3-(dimethylamino)-1,2,2-                                                    trimethyl-propyl]-1,4,4-triethyl                           353   170           1-[3-(diethylamino)-2-methyl-                                                  propyl]-1,3-dipropyl-5-methoxy                             354   171           1-[1-propyl-3-(methylamino)-                                                   propyl]-1-propyl-3,3,5-trimethyl                           355   172           1-[4-(dimethylamino)butyl]-1-                                                  methyl                                                     356   173           1-[4-(methylamino)butyl]-1-methyl                          357   174           1-(4-aminobutyl)-1-methyl                                  358   175           1-[4-(hexylamino)butyl]-1-methyl                           359   176           1-cyclobutyl-3,3-dimethyl-1-                                                   [4-(methylamino)-1,1,2-tripropyl-                                              butyl]-4-propyl                                            360   177           4,5-dimethyl-1-ethyl-1-[4-                                                     dimethylamino)-1,1,2,2,3,3-                                                    hexamethylbutyl]                                           361   178           1-(4-amino-2,3,3-trimethyl-butyl)-                                             5-bromo-1-cyclopentyl                                      362   179           1,8-diethyl-1-[3-methyl-4-                                                     (methylamino)butyl]                                        363   180           1-[1,3-diethyl-4-(diethylamino)-                                               butyl]-1-propyl-3,3,5-trimethyl                            364   181           1-[2,3-diethyl-4-(hexylamino)-                                                 butyl]-3,3-dimethyl-1,5-dipropyl                           365   182           1-methyl-1-[3-(1-pyrrolidinyl)-                                                propyl], m.p. 124 - 127° C.                         366   183           1-methyl-1-(3-piperidinopropyl)                            367   184           1-methyl-1-(3-morpholinopropyl)                            368   185           1-methyl-1-(3-piperazinopropyl)                            369   186           1-methyl-1-[3-(4-methyl-1-                                                     piperazinyl)propyl]                                        370   187           1-{3-[4-(2-hydroxyethyl)-1-                                                    piperazinyl]propyl}-1-methyl                               371   188           1-methyl-1-[(1-pyrrolidinyl)-                                                  methyl]                                                    372   189           1-methyl-1-(morpholinomethyl)                              373   190           1-ethyl-3-methyl-1-[(4-methyl-1-                                               piperazinyl)methyl]                                        374   191           1,4-dimethyl-1-(2-piperidinoethyl)                         375   192           1-ethyl-1-(2-morpholinoethyl)                              376   193           1-ethyl-1-{2-[4-(3-hydroxypropyl)-                                             1-piperazinyl]ethyl}                                       377   194           1-propyl-1-[2-(1-pyrrolidinyl)-                                                ethyl]                                                     378   195           1-propyl-1-(2-morpholinoethyl)                             379   196           1-isopropyl-1-(2-piperidinoethyl)                          380   197           3-methyl-1-(2-piperazinoethyl)-                                                1-propyl                                                   381   198           1-ethyl-1-[1-methyl-2-(4-methyl-                                               1-piperazinyl)ethyl]                                       382   199           6-benzyloxy-1-methyl-1-[2-(1-                                                  pyrrolidinyl)ethyl]                                        383   200           5-methyl-1-(2-piperidinoethyl)-                                                1-propyl                                                   384   201           1-cyclopropyl-1-(1,1-diethyl-2-                                                morpholinoethyl)-3,3-dimethyl-6-                                               ethoxy                                                     385   202           8-acetoxy-1-ethyl-3,3,4,4-                                                     tetramethyl-1-(2-methyl-3-                                                     piperazinopropyl)                                          386   203           1-cyclopropyl-4,6-dimethyl-1-                                                  {3-[4-(2-hydroxyethyl)-1-piperazin-                                            yl]-1,1,2,2-tetramethylpropyl}                             387   204           1,3-dimethyl-1-[2,2-dipropyl-3-                                                (1-pyrrolidinyl)propyl]                                    388   205           4,4-dimethyl-1-ethyl-1-(1,1-                                                   dimethyl-3-morpholinopropyl)                               389   206           1-cyclopropyl-1-[1,2-diethyl-3-                                                (4-propyl-1-piperazinyl)propyl]-                                               6-ethoxy                                                   390   207           1-methyl-1-[4(1-pyrrolidinyl)-                                                 butyl]                                                     391    207a         1-{4-[4-(hydroxymethyl)-1-                                                     piperazinyl]butyl}-1-methyl                                392   208           1-[1,1-diethyl-4-piperidino)butyl]                                             3,3-dimethyl-1-propyl                                      393   209           7-chloro-4,4-diethyl-1-methyl-1-                                               (4-morpholino-1,1,2,2,3-                                                       pentaethylbutyl)                                           394   210           1-butyl-6-fluoro-1-(4-piperazino-                                              1,2,3-trimethylbutyl)-3,3,4-                                                   trimethyl                                                  __________________________________________________________________________

                                      TABLE VIII                                   __________________________________________________________________________           NO. OF THE EXAMPLE                                                             IN WHICH STARTING                                                                           PRODUCT: (PREFIX LISTED BELOW)-                                   MATERIAL IS  1,3,4,9-TETRAHYDROCHLOPYRANO-                               EXAMPLE                                                                              PREPARED     [3,4-b]INDOLE                                               __________________________________________________________________________     395   211          1-methyl-1-[2-(methylamino)ethyl]                           396   212          1-(2-aminoethyl)-1-methyl                                   397   213          1-[(2-hexylamino)ethyl]-1-methyl                            398   214          1-[2-(dimethylamino)ethyl]-1-                                                  methyl, m.p. 119 - 121° C.                           399   215          1-[2-(diethylamino)ethyl]-1-                                                   methyl                                                      400   216          1-methyl-1-[3-(methylamino)propyl]                          401   217          1-(3-aminopropyl)-1-methyl                                  402   218          1-[3-(dimethylamino)propyl]-1-                                                 methyl                                                      403   219          1-[3-(hexylamino)propyl]-1-methyl                           404   220          1-[3-(diethylamino)propyl]-1-                                                  methyl                                                      405   221          1-methyl-1-[(methylamino)methyl]                            406   222          1-(aminomethyl)-1-methyl                                    407   223          1-[(dimethylamino)methyl]-1-                                                   methyl                                                      408   224          1-[(hexylamino)methyl]-1-methyl                             409   225          1-[(diethylamino)methyl]-1-                                                    methyl                                                      410   226          1-ethyl-3-methyl-1-[(methylamino)-                                             methyl]                                                     411   228          1-cyclopropyl-1-[(dimethylamino)-                                              methyl]-4-isopropyl                                         412   229          1,4-dimethyl-1-[2-(dimethylamino)-                                             ethyl]                                                      413   230          1-ethyl-1-[2-(methylamino)ethyl]                            414   231          1-(2-aminoethyl)-1-ethyl                                    415   232          1-[2-(dimethylamino)ethyl]-1-                                                  ethyl                                                       416   233          1-ethyl-1-[2-(hexylamino)ethyl]                             417   234          1-[2-(diethylamino)ethyl]-1-ethyl                           418   235          1-[2-(methylamino)ethyl]-1-propyl                           419   236          1-(aminoethyl)-1-propyl                                     420   237          1-[2-(dimethylamino)ethyl]-1-propyl                         421   238          1-[2-(hexylamino)ethyl]-1-propyl                            422   239          1-[2-(diethylamino)ethyl]-1-propyl                          423   240          1-isopropyl-1-[2-(methylamino)-                                                ethyl]                                                      424   241          1-(2-aminoethyl)-1-isopropyl                                425   242          1-[2-(diethylamino)ethyl]-1-                                                   isopropyl                                                   426   243          3-methyl-1-[2-(methylamino)ethyl]-                                             1-propyl                                                    427   245          1-[2-(dimethylamino)ethyl]-3-                                                  methyl-1-propyl                                             428   246          1-[2-(hexylamino)ethyl]-3-methyl-                                              1-propyl                                                    429   247          1-[2-(diethylamino)ethyl]-3-methyl-                                            1-propyl                                                    430   248          1-[1-methyl-2-(methylamino)ethyl]-                                             1-methyl                                                    431   249          1-(2-amino-1-methylethyl)-1-                                                   methyl                                                      432   250          1-[2-(dimethylamino)-1-methyl-                                                 ethyl]-1-methyl                                             433   251          1-[2-(hexylamino)-1-methyl-ethyl]-                                             1-methyl                                                    434   252          1-[2-(diethylamino)-1-methyl-                                                  ethyl]-1-methyl                                             435   253          1-cyclohexyl-1-[1,1-dimethyl-2-                                                (methylamino)ethyl]                                         436   254          8-methyl-1-[2-(methylamino)ethyl]-                                             1-propyl                                                    437   255          1-(2-aminoethyl)-6-bromo-1-propyl                           438   257          1-cyclopropyl-1-[1,1-diethyl-2-                                                (hexylamino)ethyl]-3,3-dimethyl-                                               6-ethoxy                                                    439   258          1-(3-amino-2-propyl-propyl)-1-                                                 cyclobutyl-3-methyl-8-nitro                                 440   259          1-[3-(dimethylamino)-1,2,2-                                                    trimethyl-propyl]-1,4,4-triethyl                            441   260          1-[3-(diethylamino)-2-methyl-                                                  propyl]-1,3-dipropyl-5-methoxy                              442   261          1-[1-propyl-3-(methylamino)-                                                   propyl]-1-propyl-3,3,5-trimethyl                            443   263          1-[4-(dimethylamino)butyl]-1-                                                  methyl                                                      444   264          1-[4-(methylamino)butyl]-1-                                                    methyl                                                      445   265          1-[4-(hexylamino)butyl]-1-methyl                            446   266          1-cyclobutyl-3,3-dimethyl-1-                                                   [4-(methylamino)-1,1,2-tripropyl-                                              butyl]-4-propyl                                             447   267          7-chloro-4,4-diethyl-1-[4-                                                     dimethylamino-1,1,2,2,3-                                                       pentaethylbutyl]-1-methyl                                   448   268          1-(4-amino-2,3,3-trimethyl-                                                    butyl)-5-bromo-1-cyclopentyl                                449   269          1,8-diethyl-1-[3-methyl-4-                                                     (methylamino)butyl]                                         450   270          1-[1,3-diethyl-4-(diethylamino)-                                               butyl]-1-propyl-3,3,5-trimethyl                             451   271          1-[2,3-diethyl-4-(hexylamino)-                                                 butyl]-3,3-dimethyl-1,5-dipropyl                            452   272          1-methyl-1-[2-(1-pyrrolidinyl)-                                                ethyl]                                                      453   273          1-methyl-1-(2-piperidinoethyl)                              454   274          1-methyl-1-(2-morpholinoethyl)                              455   275          1-methyl-1-(2-piperazinoethyl)                              456   276          1-methyl-1-[2-(4-methyl-1-                                                     piperazinyl)ethyl]                                          457   277          1-{2-[4-(2-hydroxyethyl)-1-                                                    piperazinyl]ethyl}-1-methyl                                 458   278          1-methyl-1-[3-(1-pyrrolidinyl)-                                                propyl]                                                     459   279          1-methyl-1-(3-piperidinopropyl)                             460   280          1-methyl-1-(3-morpholinopropyl)                             461   281          1-methyl-1-(3-piperazinopropyl)                             462   282          1-methyl-1-[3-(4-methyl-1-                                                     piperazinyl)propyl]                                         463   283          1-{3-[4-(2-hydroxyethyl)-1-                                                    piperazinyl]propyl}-1-methyl                                464   284          1-methyl-1-[(1-pyrrolidinyl)-                                                  methyl]                                                     465   285          1-methyl-1-(morpholinomethyl)                               466   286          1-ethyl-3-methyl-1-[(4-ethyl-1-                                                piperazinyl)methyl]                                         467   287          1,4-dimethyl-1-(2-piperidine-                                                  ethyl)                                                      468   288          1-ethyl-1-(2-morpholinoethyl)                               469   289          1-ethyl-1-{2-[4-(3-hydroxy-                                                    propyl)-1-piperazinyl]ethyl}                                470   290          1-propyl-1-[2-(1-pyrrolidinyl)-                                                ethyl]                                                      471   291          1-(2-morpholinoethyl)-1-propyl                              472   292          1-isopropyl-1-(2-piperidinoethyl)                           473   293          3-methyl-1-(2-piperazinoethyl)-                                                1-propyl                                                    474   295          1-methyl-1-[1-methyl-2-(4-                                                     methyl-1-piperazinyl)ethyl]                                 475   296          6-benzyloxy-1-methyl-1-[2-(1-                                                  pyrrolidinyl)ethyl]                                         476   297          5-methyl-1-(2-piperidinoethyl)-                                                1-propyl                                                    477   298          1-cyclopropyl-1-(1,1-diethyl-                                                  2-morpholinoethyl-3,3-dimethyl-                                                6-ethoxy                                                    478   299          8-acetoxy-1-ethyl-3,3,4,4-                                                     tetramethyl-1-(2-methyl-3-                                                     piperazinopropyl)                                           479   300          1-cyclopropyl-4,6-dimethyl-1-                                                  {3-[4-(2-hydroxyethyl)-1-                                                      piperazinyl]-1,1,2,2-                                                          tetramethylpropyl}                                          480   301          1,3-dimethyl-1-[2,2-dipropyl-                                                  3-(1-pyrrolidinyl)propyl]                                   481   302          4,4-dimethyl-1-ethyl-1-(1,1-                                                   dimethyl-3-morpholinopropyl)                                482   303          1-cyclopropyl-6-ethoxy-1-                                                      [1,2-diethyl-3-(4-propyl-1-                                                    piperazinyl)propyl]                                         483   304          1-methyl-1-[4-(1-pyrrolidinyl)-                                                butyl]                                                      484   305          1-{4-[4-(hydroxymethyl)-                                                       piperazinyl]butyl}-1-methyl                                 485   306          1-[(1,1-diethyl-4-piperidine)-                                                 butyl]-3,3-dimethyl-1-propyl                                486   307          7-chloro-4,4-diethyl-1-methyl-                                                 1-(4-morpholino-1,1,2,2,3-                                                     pentaethylbutyl)                                            487   308          1-butyl-6-fluoro-1-(4-                                                         piperazino-1,2,3-trimethylbutyl)                                               3,3,4-trimethyl                                             __________________________________________________________________________

EXAMPLE 488 1,9DIMETHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID (VII; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ AND R⁶ = H,X = O and Z = CH₂ COOH

1Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (10 g., 0.04 mole), prepared as described in Example 1, in 150 ml. of tetrahydrofuran is added dropwise to a stired suspension of sodium hydride (4.4 g. of 55% dispersion) in 200 ml. of tetrahydrofuran. This mixture is heated at 50° C. with stirring for 2 hr. Methyl iodide (14.2 g. 0.1 mole) is added dropwise and heating and stirring is continued for a further 2 hr.

After cooling, water is added until the solution is clear. The tetrahydrofuran is evaporated off under reduced pressure, the residue is partitioned between water and benzene. The aqueous phase is washed once with benzene, made acidic with HCl, and extracted with benzene (3x). The organic phase is washed with water, dried over sodium sulfate and treated with charcoal. The organic layer is evaporated. The residue is crystallized from benzene and then ether-petroleum ether to afford the title compound, m.p. 105° - 108° C., nmr (CDCl₃) δ1.73 (S, 3H), 2.83 (t, J = 5.5, 2H), 3.0 (2H), 3.68 (3H), 4.08 (t, J = 5.5, 2H), 7.34 (4H), 9.47 (1H).

In the same manner but replacing methyl iodide with an equivalent amount of ethyl iodide, or propyl iodide, the N-ethyl analog of the title compound, 9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, m.p. 134° - 136° C., and the N-propyl analog of the title compound, 1-methyl-9-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, m.p. 120° - 122° C., are obtained respectively.

By following the procedure of Example 488 but using as starting material an equivalent amount of the acid compounds of formula VII, in which R⁷ is hydrogen, described in Examples 1 to 125, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate organic halide, then the corresponsing N-alkylated acid compounds of formula I are obtained. Examples of these latter compounds are listed as products in Tables IX and X together with the appropriate starting material of formula VII and organic halide used for their preparation. In each case the starting material is noted by the Example in which it is prepared.

                                      TABLE IX                                     __________________________________________________________________________           NO. OF THE EXAMPLE        PRODUCT: [(PREFIX LISTED BELOW)-                     IN WHICH STARTING         1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                     MATERIAL IS   ORGANIC     INDOLE-(SUFFIX LISTED BELOW)]                  EXAMPLE                                                                              PREPARED      HALIDE         PREFIX//SUFFIX                              __________________________________________________________________________     489   1             CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-methyl//acetic acid,                                                 m.p. 103 - 105° C.                      490   1             CH.sub.2CHBr                                                                               1-methyl9-vinyl//acetic acid                   491   1                                                                                             ##STR54##  1-methyl-9-propargyl//acetic acid              492   2             n-C.sub.3 H.sub.7 I                                                                        1-methyl-9-propyl//propionic acid              493   2             CH.sub.3 I  1,9-dimethyl//propionic acid                   494   2                                                                                             ##STR55##  1-methyl-9-phenethyl//propionic acid           495   2             1-(3-chloropropyl)                                                                         1-methyl-9-(3-piperidinopropyl)//                                  piperazine  propionic acid                                 496   4             1-(2-chloroethyl)-                                                                         1-methyl-9-[2-(1-pyrrolidinyl)-                                    pyrrolidine ethyl]//carboxylic acid                        497   6                                                                                             ##STR56##                                                                                  ##STR57##                                     498   7             CH.sub.3 I  6-hydroxy-1,3,3,9-tetramethyl//                                                carboxylic acid                                499   8             CH.sub.3 CHCHBr                                                                            8-ethyl-9-(1-propenyl)-1-propyl//                                              carboxylic acid                                500   10            C.sub.2 H.sub.5 Br                                                                         1-cyclopentyl-4,4,9-triethyl-3,3-                                              dimethyl//carboxylic acid                      501   12            CH.sub.3 I  1-ethyl-9-methyl//acetic acid                  502   12            C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl//acetic acid                       503   12            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-ethyl//acetic acid                   504   12            2-(dimethylamino)-                                                                         9-[2-(dimethylamino)ethyl]//acetic                                 ethyl chloride                                                                             acid                                           505   13            CH.sub.3 I  9-methyl-1-propyl//acetic acid                 506   13            n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl//acetic acid                      507   13            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-propyl//acetic acid                  508   13            CH.sub.2C(CH.sub.3)CH.sub.2 Br                                                             9-methallyl-1-propyl//acetic acid              509   14                                                                                            ##STR58##  9-benzyl-1-isopropyl//acetic acid              510   14            CH.sub.2CHBr                                                                               1-isopropyl-9-vinyl//acetic acid               511   15            n-C.sub.3 H.sub.7 Cl                                                                       1,9-dipropyl-3-methyl//acetic acid             512   16            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1,4-diethyl-3-methyl//                                                 acetic acid                                    513   17            CH.sub.3 I  α,1,9-trimethyl//acetic acid             514   18            n-C.sub.3 H.sub.7 Cl                                                                       1-cyclohexyl-α,α-dimethyl-9-                                       propyl//acetic acid                            515   19            CH.sub.2CHCH.sub.2 Br                                                                      9-allyl-1-t-butyl//acetic acid                 516   20            CH.sub.2CHCH.sub.2                                                                         9-allyl-1-butyl//acetic acid                   517   23            CH.sub.3 Cl 1,9-dimethyl-6-methoxy//acetic                                                 acid, m.p. 129 - 132° C.                518   28            CH.sub.2CHBr                                                                               6-nitro-1-propyl-9-vinyl//acetic                                               acid                                           519   32                                                                                            ##STR59##                                                                                  ##STR60##                                     520   34            CH.sub.2 CHCH.sub.2 Br                                                                     9-allyl-1-t-butyl-α,α-diisopro                                     pyl-                                                                           3,3,4,4,5-pentaethyl//acetic acid              521   37            C.sub.2 H.sub.5 I                                                                          7-hydroxy-1-(propyl)-β,β,9-                                          triethyl//propionic acid                       522   38            CH.sub.3 I  1-cyclobutyl-3,9-dimethyl-8-                                                   nitro-α-propyl//propionic acid           523   41            CH.sub.2C(CH.sub.3)CH.sub.2 Cl                                                             1,4,4-triethyl-9-methallyl-α,α                                     ,β-                                                                       3-tetramethyl//propionic acid                  524   45                                                                                            ##STR61##  1-methyl-6-nitro-α,α,β,.b                                     eta.,3-penta-  ethyl-9-phenethyl//propioni                                     c acid                                         525   47            1-(3-chloro-                                                                               1-cyclopropyl-α,β-diethyl-6-                            propyl)piperazine                                                                          ethoxy-9-(3-piperidinopropyl)//                                                propionic acid                                 526   48            CH.sub.3 I  1,9-dimethyl//butyric acid                     527   48                                                                                            ##STR62##  9-benzyl-1-methyl//butyric acid                528   49            C.sub.2 H.sub.5 Cl                                                                         1,9-diethyl-γ,3-dimethyl//butyric                                        acid                                           529   51            CH.sub.2CHBr                                                                               1-cyclobutyl-3,3-dimethyl-β,γ,.                                     gamma.,-                                                                       4-tetrapropyl-9-vinyl//butyric                                                 acid                                           530   52            CH.sub.2CHBr                                                                               7-chloro-α,β,β,γ,.ga                                     mma.,4-heptaethyl-1-                                                           methyl-9-vinyl//butyric acid                   531   58            C.sub.2 H.sub.5 I                                                                          α-methyl-1,8,9-triethyl//butyric                                         acid                                           532   62            CH.sub.3 I  α,β-diethyl-1,5-dipropyl-3,3,9-                                     N                                                                              trimethyl//butyric acid                        532a  64a           CH.sub.3 I  1,5,9-trimethyl//acetic acid,                                                  m.p. 132 - 134° C.                      532b  25            C.sub.2 H.sub.5 Br                                                                         6-benzyloxy-9-ethyl-1-methyl//                                                 acetic acid, nmr (CDCl.sub.3) δ                                          1.73                                                                           (s,3H), 5.12 (s,2H).                           532c  64b           CH.sub.3 I  5-chloro-1,9-dimethyl//acetic                                                  acid, m.p. 105 - 110° C.                532d  784           CH.sub.3 I  6-benzyloxy-1,9-dimethyl//acetic                                               acid, m.p. 167 - 168° C.                __________________________________________________________________________

                                      TABLE X                                      __________________________________________________________________________           NO. OF THE EXAMPLE       PRODUCT: [(PREFIX LISTED BELOW)-                      IN WHICH STARTING        1,3,4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                  MATERIAL IS   ORGANIC    INDOLE-(SUFFIX LISTED BELOW]                    EXAMPLE                                                                              PREPARED      HALIDE        PREFIX//SUFFIX                               __________________________________________________________________________     533   3             CH.sub.2CHCH.sub.2 Br                                                                     9-allyl-1-methyl//acetic acid                   534   3             CH.sub.3 I 1,9-dimethyl//acetic acid                       535   3             4-(2-chloroethyl)-                                                                        1-methyl-9-(2-morpholinoethyl)//                                    morpholine acetic acid                                     536   96            n-C.sub.3 H.sub.7 I                                                                       1-methyl-9-propyl//propionic acid               537   96            CH.sub.3 I 1,9-dimethyl//propionic acid                    538   96                                                                                            ##STR63## 1-methyl-9-propargyl//propionic acid            539   96            CH.sub.2CHCH.sub.2 Cl                                                                     9-allyl-1-methyl//propionic acid                540   65            CH.sub.3 I 1,9-dimethyl//carboxylic acid                   541   65            1-(3-chloropropyl)-                                                                       1-methyl-9-(3-piperidinopropyl)//                                   piperidine carboxylic acid                                 542   68            CH.sub.3 I 6-hydroxy-1-(1-propyl)-3,3,9-                                                  trimethyl//carboxylic acid                      543   70            CH.sub.3 CHCHBr                                                                           1-cyclopropyl-4-isopropyl-9-                                                   (1-propenyl)//carboxylic acid                   544   73            CH.sub.3 I 1-ethyl-9-methyl//acetic acid                   545   73            C.sub.2 H.sub.5 Cl                                                                        1,9-diethyl//acetic acid                        546   73            4-(2-chloroethyl)-                                                                        1-ethyl-9-(2-morpholinoethyl)//                                     morpholine acetic acid                                     547   73                                                                                            ##STR64## 1-ethyl-9-propargyl//acetic acid                548   74            CH.sub.3 I 9-methyl-1-propyl//acetic acid                  549   74            n-C.sub.3 H.sub.7 Cl                                                                      1,9-dipropyl//acetic acid                       550   74            CH.sub.2CHCH.sub.2 Br                                                                     9-allyl-1-propyl//acetic acid                   551   74            CH.sub.2C(CH.sub.3)CH.sub.2 Br                                                            9-methallyl-1-propyl//acetic acid               552   75            CH.sub.3 I 9-methyl-1-isopropyl//acetic acid               553   75            CHCHBr     1-isopropyl-9-vinyl//acetic acid                554   76            n-C.sub.3 H.sub.7 Cl                                                                      1,9-dipropyl-3-methyl//acetic acid              555   76                                                                                            ##STR65## 9-benzyl-3-methyl-1-propyl//acetic acid         556   78            CH.sub.3 I α,1,9-trimethyl//acetic acid              557   79            n-C.sub.3 H.sub.7 Cl                                                                      1-cyclohexyl-α,α-dimethyl-9-                                       propyl//acetic acid                             558   84            CH.sub.3 Cl                                                                               1,9-dimethyl-6-methoxy//acetic acid             559   89            CH.sub.2CHBr                                                                              α,α-diethyl-1-methyl-9-vinyl-8-                                    O                                                                              fluoro//acetic acid                             560   93            C.sub.2 H.sub.5 Cl                                                                        α,3-dimethyl-1,9-diethyl-1-phenyl-                                       4,4,5-tripropyl//acetic acid                    561   95            CH.sub.2CHCH.sub.2 Br                                                                     9-allyl-1-t-butyl-α,α-diisoprop                                    yl-                                                                            3,3,4,4,5-pentaethyl//acetic acid               562   98            C.sub.2 H.sub.5 I                                                                         7-hydroxy-1-propyl-β,β,9-                                            triethyl//propionic acid                        563   99            CH.sub.3 I 1-cyclobutyl-3,9-dimethyl-8-nitro-                                             α-propyl//propionic acid                  564   106           CH.sub.2CHCl                                                                              1-methyl-6-nitro-α,α,β,.be                                    ta.,3-penta-                                                                   ethyl-9-vinyl//propionic acid                   565   108           C.sub.2 H.sub.5 Cl                                                                        1-cyclopropyl-6-ethoxy-α,β,9-                                       triethyl//propionic acid                        566   109           CH.sub.3 I 1,9-dimethyl//butyric acid                      567   109           CH.sub.2CHCH.sub.2 Cl                                                                     9-allyl-1-methyl//butyric acid                  568   110           C.sub.2 H.sub.5 Cl                                                                        1,9-diethyl-γ,3-dimethyl//butyric                                        acid                                            569   112           CH.sub.2CHBr                                                                              1-cyclobutyl-3,3-dimethyl-β,γ,.g                                    amma.,4-                                                                       tetrapropyl-9-vinyl//butyric acid               570   119           C.sub.2 H.sub.5 I                                                                         α-methyl-1,8,9-triethyl//butyric                                         acid                                            __________________________________________________________________________

EXAMPLE 571

By following the procedure of Example 488 but using as the starting material an equivalent amount of the ester compounds of formula I in which R⁷ is hydrogen, obtained prior to hydrolysis in Examples 1 and 3 to 125, inclusive, instead of 1methyl 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of the appropriate organic halide, then the corresponding N-alkylated ester compound of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl or phenyl(lower)alkyl is obtained.

For example, when following the procedure of Example 488, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by an equivalent amount of its corresponding ethyl ester, described in Example 1, and then use of the same alkyl halide, methyl iodide, affords 1,9-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1acetic acid ethyl ester.

Similarly, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by an equivalent amount of 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester, described in Example 3, affords 1,9-dimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester.

By following the procedure of Example 126 but using as starting material an equivalent amount of one of the N-alkylated acid compounds of formula I, described in Examples 488 to 570, inclusive, instead of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, and using an equivalent amount of an appropriate amine such as ammonia or a primary or secondary amine, described in Example 126, then the corresponding amide compound of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl phenyl(lower)alkyl and amino(lower)alkyl is obtained. Examples of such amides are listed as products in Tables XI, XII, XIII, and XIV together with the appropriate starting material, noted by the example in which it is prepared, and the amine used for the preparation of the amide.

                                      TABLE XI                                     __________________________________________________________________________           NO. OF THE EXAMPLE   PRODUCT: [(PREFIX LISTED BELOW)-                          IN WHICH STARTING    1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          MATERIAL IS          INDOLE-1-(SUFFIX LISTED BELOW)]                     EXAMPLE                                                                              PREPARED      AMINE  PREFIX//SUFFIX                                      __________________________________________________________________________     572   488 (title compound)                                                                         (CH.sub.3).sub.2 NH                                                                   N,N,1,9-tetramethyl//acetamide                      573   488 (title compound)                                                                         CH.sub.3 NH.sub.2                                                                     N,1,9-trimethyl//acetamide, m.p.                                               136 - 138° C.                                574   488 (title compound)                                                                         NH.sub.3                                                                              1,9-dimethyl//acetamide, m.p.                                                  105 - 106° C.                                575   488 (title compound)                                                                         n-C.sub.6 H.sub.13 NH.sub.2                                                           1,9-dimethyl-N-hexyl//acetamide                     576   488 (title compound)                                                                         (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-1,9-dimethyl//acetamide                 577   488 (N-ethyl analog)                                                                         (CH.sub.3).sub.2 NH                                                                   9-ethyl-N,N,1-trimethyl//acetamide                  578   488 (N-ethyl analog)                                                                         CH.sub.3 NH.sub.2                                                                     N,1-dimethyl-9-ethyl//acetamide,                                               m.p. 108 - 109° C.                           579   488 (N-ethyl analog)                                                                         NH.sub.3                                                                              9-ethyl-1-methyl//acetamide, m.p.                                              130 - 133° C.                                580   488 (N-propyl analog)                                                                        (CH.sub.3).sub.2 NH                                                                   9-propyl-N,N,1-trimethyl//acetamide                                            m.p. 84 - 87° C.                             581   488 (N-propyl analog)                                                                        CH.sub.3 NH.sub.2                                                                     N,1-dimethyl-9-propyl//acetamide                    582   489           CH.sub.3 NH.sub.2                                                                     9-allyl-N,1-dimethylacetamide                       583   491           (CH.sub.3).sub.2 NH                                                                   9-propargyl-N,N,1-trimethyl//                                                  acetamide                                           584   493           (CH.sub.3).sub.2 NH                                                                   N,N,1,9-tetramethyl//propionamide                   585   493           CH.sub.3 NH.sub.2                                                                     N,1,9-trimethyl//propionamide, m.p.                                            148 - 150° C.                                586   493           (C.sub.2 H.sub.5).sub.2 NH                                                            1,9-dimethyl-N,N-diethyl//                                                     propionamide                                        587   495           NH.sub.3                                                                              1-methyl-9-(3-piperidinopropyl)//                                              propionamide                                        588   495           (CH.sub.3).sub.2 NH                                                                   9-(3-piperidinopropyl-N,N,1-                                                   trimethyl//propionamide                             589   497           CH.sub.3 NH.sub.2                                                                     1,3-diisopropyl-N,6-dimethyl-9-                                                propargyl//carboxamide                              590   498           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N-diethyl-6-hydroxy-1,3,3,9-                                                 tetramethyl//carboxamide                            591   501           CH.sub.3 NH.sub.2                                                                     N,9-dimethyl-1-ethyl//acetamide                     592   503           (C.sub.2 H.sub.5).sub.2 NH                                                            9-allyl-N,N,1-triethyl//acetamide                   593   504           (CH.sub.3).sub.2 NH                                                                   N,N-dimethyl-9-[2-(dimethylamino)-                                             ethyl]-1-ethyl//acetamide                           594   505           CH.sub.3 NH.sub.2                                                                     N,9-dimethyl-1-propyl//acetamide                    595   507           (C.sub.2 H.sub.5).sub.2 NH                                                            9-allyl-N,N-diethyl-1-propyl//                                                 acetamide                                           596   514           CH.sub.3 NH.sub.2                                                                     1-cyclohexyl-9-propyl-N,α,α-                                       trimethyl//acetamide                                597   516           n-C.sub.6 H.sub.13 NH.sub.2                                                           9-allyl-1-butyl-N-hexyl//acetamide                  598   517           (CH.sub.3).sub.2 NH                                                                   6-methoxy-N,N,1,9-tetramethyl//                                                acetamide, m.p. 118 - 120° C.                599   519           CH.sub.3 NH.sub.2                                                                     1-ethyl-9-propargyl-4,4,5-tripropyl-                                           N,α,3-trimethyl//acetamide                    600   524           (C.sub.2 H.sub.5).sub.2 NH                                                            N,N,α,α,β,β,3-heptaethyl-                                1-                                                                             methyl-6-nitro-9-phenethyl//                                                   propionamide                                        601   525           (C.sub.2 H.sub.5).sub.2 NH                                                            1-cyclopropyl-6-methoxy-N,N,α,β,9-                                  pentaethyl-9-vinyl//propionamide                    602   526           CH.sub.3 NH.sub.2                                                                     N,1,9-trimethyl//butyramide                         603   527           (CH.sub.3).sub.2 NH                                                                   9-benzyl-N,N,1-trimethyl//                                                     butyramide                                          604   528           NH.sub.2                                                                              1,9-diethyl-γ,3-dimethyl//                                               butyramide                                          605   532           CH.sub.3 NH.sub.2                                                                     α,β-diethyl-1,5-dipropyl-N,3,3,9-                                   tetramethyl//butyramide                             605a  532a          (CH.sub.3).sub.2 NH                                                                   N,N,1,5,9-pentamethyl//acetamide,                                              nmr (CDCl.sub.3) δ 1.75 (s,3H), 2.66                                     (s,3H), 2.96 (s,3H), 3.08 (s,3H),                                              3.78 (s,3H)                                         605b  532b          (CH.sub.3).sub.2 NH                                                                   6-benzyloxy-9-ethyl-N,N,1-trimethyl//                                           ##STR66##                                          605c  532c          (CH.sub.3).sub.2 NH                                                                   5-chloro-N,N,1,9-tetramethyl//                                                 acetamide, nmr (CDCl.sub.3) δ 1.72                                       (s,3H), 2.93 (s,3H), 3.80 (s,3H),                                              3.77 (s,3H)                                         605d  532d          (CH.sub.3).sub.2 NH                                                                   6-benzyloxy-N,N,1,9-tetramethyl//                                              acetamide, nmr (CDCl.sub.3) δ 1.73                                       (s,3H), 2.95 (s,3H), 3.05 (s,3H),                                              3.75 (s,3H), 5.12 (s,2H)                            __________________________________________________________________________

                                      TABLE XII                                    __________________________________________________________________________           NO. OF THE EXAMPLE  PRODUCT: (PREFIX LISTED BELOW)-                            IN WHICH STARTING   (1,3,4,9-TETRAHYDROPYRANO[3,4-b]-                          MATERIAL IS         INDOLE-1-YL)-(SUFFIX LISTED BELOW)]                  EXAMPLE                                                                              PREPARED    AMINE   PREFIX//SUFFIX                                       __________________________________________________________________________     606   488 (title compound)                                                                       pyrrolidine                                                                            1-[(1,9-dimethyl//acetyl]pyrrolidine                                           nmr (CDCl.sub.3) δ 177(3H), 2.82(2H),                                    3.78(3H),                                            607   488 (title compound)                                                                       piperidine                                                                             1-[(1,9-dimethyl//acetyl]piperidine                  608   488 (title compound)                                                                       morpholine                                                                             1-[(1,9-dimethyl//acetyl]morpholine,                                           nmr(CDCl.sub.3) δ 1.73(3H), 3.03(2H),                                    3.70(3H)                                             609   488 (title compound)                                                                       N-methyl-                                                                              1-methyl-4-[1,9-dimethyl//acetyl]-                                     piperazine                                                                             piperazine, ν.sub.max.sup.CHCl 3 1640                                       cm.sup.-.sup.1                                       610   488 (N-ethyl analog)                                                                       pyrrolidine                                                                            1-[(9-ethyl-1-methyl//acetyl]-                                                 pyrrolidine                                          611   488 (N-ethyl analog)                                                                       piperidine                                                                             1-[(9-ethyl-1-methyl//acetyl]-                                                 piperidine                                           612   488 (N-propyl analog)                                                                      morpholine                                                                             1-[(1-methyl-9-propyl//acetyl]-                                                morpholine                                           613   488 (title compound)                                                                       N-piperazine-                                                                          1-(2-hydroxyethyl)-4-[1,9-dimethyl//                                   ethanol acetyl]piperazine, γ.sub.max.sup.film                                    1625 cm.sup.-.sup.1                                  614   492         pyrrolidine                                                                            1-[(1-methyl-9-propyl//propionyl]-                                             pyrrolidine                                          615   493         piperidine                                                                             1-[(1,9-dimethyl//propionyl]-                                                  piperidine                                           616   494         morpholine                                                                             1-[(1-methyl-9-phenethyl//propionyl]-                                          morpholine                                           617   495         piperazine                                                                             1-[1-methyl-9-(3-piperidinopropyl)//                                           propionyl]piperazine                                 618   496         pyrrolidine                                                                            1-{1-methyl-9-[2-(1-pyrrolidinyl)-                                             ethyl]//carbonyl}pyrrolidine                         619   501         morpholine                                                                             1-[(1-ethyl-9-methyl//acetyl]-                                                 morpholine                                           620   502         N-piperazine-                                                                          1-(3-hydroxypropyl)-4-[1,9-diethyl//                                   propanol                                                                               acetyl]piperazine                                    621   505         pyrrolidine                                                                            1-[(9-methyl-1-propyl//acetyl]-                                                pyrrolidine                                          622   507         morpholine                                                                             1-[(9-allyl-1-propyl//acetyl]-                                                 morpholine                                           623   509         piperidine                                                                             1-[(9-benzyl-1-isopropyl//acetyl]-                                             piperidine                                           624   511         piperazine                                                                             1-[(1,9-dipropyl-3-methyl//acetyl]-                                            piperazine                                           625   513         N-ethyl-                                                                               1-ethyl-4-[(α,1,9-trimethyl-α//                            piperazine                                                                             acetyl]piperazine                                    626   525         N-propyl-                                                                              1-propyl-4-[(1-cyclopropyl-α,β-                             piperazine                                                                             diethyl-6-ethoxy-9-(3-piperidino-                                              propyl//propionyl]piperazine                         627   566         pyrrolidine                                                                            1-[(1,9-dimethyl//butyryl]-                                                    pyrrolidine                                          628   527         N-piperazine-                                                                          9-benzyl-1-(hydroxymethyl)-4-                                          methanol                                                                               [(1-methyl//butyryl]piperazine                       629   530         morpholine                                                                             1-[(7-chloro-α,β,β,γ,.gamm                               a.,4,4-                                                                        heptaethyl-1-methyl-9-vinyl//                                                  butyryl]morpholine                                   __________________________________________________________________________

                                      TABLE XIII                                   __________________________________________________________________________           NO. OF THE EXAMPLE PRODUCT:[(PREFIX LISTED BELOW)-1,3-                         IN WHICH STARTING  4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                            MATERIAL IS        INDOLE-1-(SUFFIX LISTED BELOW)]                       EXAMPLE                                                                              PREPARED      AMINE                                                                                  PREFIX//SUFFIX                                     __________________________________________________________________________     630   534          (CH.sub.3).sub.2 NH                                                                  N,N,1,9-tetramethyl//acetamide                        631   534          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//acetamide                            632   534          NH.sub.3                                                                             1,9-dimethyl//acetamide                               633   534          n-C.sub.6 H.sub.13 NH.sub.2                                                          1,9-dimethyl-N-hexyl//acetamide                       634   534          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-1,9-dimethyl//acetamide                   635   533          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//acetamide                    636   537          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//propionamide                         637   537          (C.sub.2 H.sub.5).sub.2 NH                                                           1,9-dimethyl-N,N-diethyl//propion-                                             amide                                                 638   539          NH.sub.3                                                                             9-allyl-1-methyl//propionamide                        639   539          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//propionamide                 640   541          CH.sub.3 NH.sub.2                                                                    N,1-dimethyl-9-(3-piperidinopropyl)//                                          carboxamide                                           641   542          (C.sub.2 H.sub.5).sub.2 NH                                                           N,N-diethyl-6-hydroxy-1-propyl-                                                3,3,9-trimethyl//carboxamide                          642   544          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-ethyl//acetamide                       643   546          (C.sub.2 H.sub.5).sub.2 NH                                                           9-(2-morpholinoethyl)-N,N,1-                                                   triethyl//acetamide                                   644   547          (CH.sub.3).sub.2 NH                                                                  N,N-dimethyl-1-ethyl-9-propargyl//                                             acetamide                                             645   548          CH.sub.3 NH.sub.2                                                                    N,9-dimethyl-1-propyl//acetamide                      646   550          (C.sub.2 H.sub.5).sub.2 NH                                                           9-allyl-N,N-diethyl-1-propyl//                                                 acetamide                                             647   557          CH.sub.3 NH.sub.2                                                                    1-cyclohexyl-9-propyl-N,α,α-                                       trimethyl//acetamide                                  648   558          (CH.sub.3).sub.2 NH                                                                  6-methoxy-N,N,1,9-tetramethyl//                                                acetamide                                             649   564          (C.sub.2 H.sub.5).sub.2                                                              N,N,α,α,β,β,3-heptaethyl-1-                              methyl-                                                                        6-nitro-9-vinyl//propionamide                         650   565          (C.sub.2 H.sub.5).sub.2 NH                                                           1-cyclopropyl-6-ethoxy-N,N,α,β,9-                                   pentaethyl//propionamide                              651   566          CH.sub.3 NH.sub.2                                                                    N,1,9-trimethyl//butyramide                           652   567          (CH.sub.3).sub.2 NH                                                                  9-allyl-N,N,1-trimethyl//butyramide                   653   568          NH.sub.2                                                                             1,9-diethyl-γ,3-dimethyl//butyramide            __________________________________________________________________________

                                      TABLE XIV                                    __________________________________________________________________________           NO. OF THE EXAMPLE    PRODUCT:[(PREFIX LISTED BELOW)-1,3-                      IN WHICH STARTING     4,9-TETRAHYDROTHIOPYRANO[3,4-b]-                         MATERIAL IS           INDOLE-1-YL)-(SUFFIX LISTED BELOW)]                EXAMPLE                                                                              PREPARED      AMINE      PREFIX//SUFFIX                                  __________________________________________________________________________     654   533          pyrrolidine                                                                             1-[(9-allyl-1-methyl//acetyl]-                                                 pyrrolidine                                        655   534          piperidine                                                                              1-[(1,9-dimethyl//acetyl]piperidine                656   535          morpholine                                                                              1-[(1-methyl-9-(2-morpholino-                                                  ethyl)//acetyl]morpholine                          657   536          pyrrolidine                                                                             1-[(1-methyl-9-propyl//propionyl]-                                             pyrrolidine                                        658   537          piperidine                                                                              1-[(1,9-dimethyl//propionyl]-                                                  piperidine                                         659   538          morpholine                                                                              1-[(1-methyl-9-propargyl//                                                     propionyl]morpholine                               660   539          piperazine                                                                              1-[9-allyl-1-methyl//propionyl]-                                               piperazine                                         661   539          N-methyl-                                                                               1-methyl-4-[9-allyl-1-methyl//                                        piperazine                                                                              propionyl]piperazine                               662   540          pyrrolidine                                                                             1-[(1,9-dimethyl//carbonyl]-                                                   pyrrolidine                                        663   541          morpholine                                                                              1-{(1-methyl-9-(3-piperidino-                                                  propyl//carbonyl}morpholine                        664   544          morpholine                                                                              1-[(1-ethyl-9-methyl//acetyl]-                                                 morpholine                                         665   547          N-piperazine-                                                                           1-(3-hydroxypropyl)-4-[(1-ethyl-                                      propanol 9-propargyl//acetyl]piperazine                     666   548          pyrrolidine                                                                             1-[(9-methyl-1-propyl//acetyl]-                                                pyrrolidine                                        667   549          morpholine                                                                              1-[(1,9-dipropyl//acetyl]-                                                     morpholine                                         668   552          piperidine                                                                              1-[(1-isopropyl-9-methyl//                                                     acetyl]piperidine                                  669   555          piperazine                                                                              1-[9-benzyl-3-methyl-1-propyl//                                                acetyl]piperidine                                  670   556          N-ethyl- 1-ethyl-4-[α,1,9-trimethyl//                                    piperazine                                                                              acetyl]piperazine                                  671   565          N-propyl-                                                                               1-propyl-4-[(1-cyclopropyl-6-                                         pyrazine ethoxy-α,β,9-triethyl//propionyl]-                                  O                                                                              piperazine                                         672   566          pyrrolidine                                                                             1-[(1,9-dimethyl//butyryl]-                                                    pyrrolidine                                        673   567          N-piperazine-                                                                           1-(hydroxymethyl)-4-[(9-allyl-1-                                      methanol methyl//butyryl]piperazine                         __________________________________________________________________________

EXAMPLE 674 1,9-DIMETHYL-1-[2-(DIMETHYLAMINO)ETHYL]-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE[I; R¹ = CH₃, R², R³, R⁴, R⁵, AND R⁶ = H, R⁷ = CH₃, X = O AND Y = CH₂ CH₂ N(CH₃)₂ ]

A solution of N,N,1,9tetramethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1(12.0 g), described in Example 572, in dry tetrahydrofuran (100 ml.) is added dropwise to a mechanically stirred mixture of lithium aluminium hydride (5 g) in dry tetrahydrofuran (THF) (100 ml.). The mixture is heated at reflux for twenty hours under nitrogen. Water-THF (1:1, 50 ml.) is added to destroy the excess hydride. The mixture is filtered through celite, diluted with water (300 ml.) and extracted three times with ether. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to yield the title compound, nmr (CDCl₃) δ 1.66 (3H), 2.70 (6H), 3.83 (3H).

The corresponding hdyrochloric acid addition salt, 1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, has m.p. 229° - 230° C. after crystallization from methylene dichloride-benzene.

The title compound is resolved by the use of d- and i- di-p-toluoyl-tartaric acid into the optical isomer, (-)-1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, [α]_(D) ^(CHCl).sbsb.3 = -41.5° and its corresponding (+) antipode having [α]_(D) ^(CHCl) .sbsb.334.6°.

By following the procedure of Example 674 but using as a starting material an equivalent amount of one of the N-alkylated amide compounds of formula VII, described in Examples 573 to 673 instead of N,N1,9-tetramethyl-1,3,4,9-tetrahydro[3,4-b]indole-1-acetamide then the corresponding N-alkylated amine compound of formula I is obtained. Examples of such compounds are listed as products in Tables XV and XVI together with the appropriate starting material. In each case the starting material is noted by the example in which it is prepared.

                                      TABLE XV                                     __________________________________________________________________________           NO. OF THE EXAMPLE                                                             IN WHICH STARTING                                                                            PRODUCT: (PREFIX LISTED BELOW)-                            EXAMPLE                                                                              MATERIAL IS PREPARED                                                                         1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE                      __________________________________________________________________________     675   573           1,9-dimethyl-1-[2-(methylamino)ethyl]                                          nmr(CDCl.sub.3) δ 1.10(1H), 1.66(S, 3H), 2.33                            (S,3H), corresponding hydrobromic acid                                         addition salt has m.p. 223 - 225° C.                676   574                                                                                           ##STR67##                                                 677   575           1,9-dimethyl-1-[2-(hexylamino)ethyl]                       678   576           1-[2-(diethylamino)ethyl]-1,9-dimethyl,                                        nmr (CDCl.sub.3) δ 0.94 (t, 6H), 1.06 (S, 3H),                           2.50 (m, 10H).                                             679   577           1-[2-(dimethylamino)ethyl]-9-ethyl-1-                                          methyl, nmr (CDCl.sub.3) δ 1.39 (3H), 1.70                               (3H),                                                                          2.73 (m, 12H), corresponding hydrochloric                                      acid addition salt has m.p. 202 - 205° C.           680   578           9-ethyl-1-methyl-1-[2-(methylamino)ethyl]                  681   579           1-(2-aminoethyl)-9-ethyl-1-methyl                          682   580           1-[2-(dimethylamino)ethyl]-1-methyl-9-                                         propyl, nmr (CDCl.sub.3), δ 1.00 (t, 3H), 1.65                           (S, 3H), corresponding maleic acid                                             addition salt has m.p. 125 - 126° C.                683   581           1-methyl-1-[2-(methylamino)ethyl]-9-propyl                 684   582           9-allyl-1-methyl-1-[2-(methylamino)ethyl]                  685   583           1-[2-(diethylamino)ethyl]-1-methyl-9-                                          propargyl                                                  686   584           1,9-dimethyl-1-[3-(dimethylamino)propyl],                                      nmr (CDCl.sub.3) δ 1.60 (3H), 2.68 (6H),                                 corresponding maleic acid addition salt                                        has m.p. 115 - 118° C.                              687   585           1,9-dimethyl-1-[3-(methylamino)propyl] nmr                                     (CDCl.sub.3) δ 1.6(3H), 2.9(3H), 3.6(3H),                                corresponding hydrochloric acid addition                                       salt has m.p. 194 - 196° C.                         688   586           1-[3-(diethylamino)propyl]-1,9-dimethyl                    689   587           1-(3-aminopropyl)-1-methyl-9-(3-                                               piperidinopropyl)                                          690   588           1-[3-(dimethylamino)propyl]-1-methyl-9-                                        (3-piperidinopropyl)                                       691   589           1,3-diisopropyl-1-methyl-1-(methylamino)-                                      methyl-9-propargyl                                         692   590           1-(diethylamino)methyl-6-hydroxy-1,3,3,9-                                      tetramethyl                                                693   591           1-ethyl-9-methyl-1-[2-(methylamino)ethyl]                  694   592           9-allyl-1-[2-(diethylamino)ethyl]-1-ethyl                  695   593           1,9-bis-[2-(dimethylamino)ethyl]-1-ethyl                   696   594           9-methyl-1-[2-(methylamino)ethyl]-1-propyl                 697   595           9-allyl-1-[2-(diethylamino)ethyl]-1-propyl                 698   596           1-cyclohexyl-1-[1,1-dimethyl-2-(methyl-                                        amino)ethyl]-9-propyl                                      699   597           9-allyl-1-butyl-1-[2-(hexylamino)ethyl]                    700   598           1,9-dimethyl-1-[2-(dimethylamino)ethyl]-                                       6-methoxy, nmr(CDCl.sub.3) δ 2.60(S,3H), 3.85                            (S,3H), corresponding maleic acid addition                                     salt has m.p. 109 - 111° C.                         701   599           1-ethyl-3-methyl-1-[1-methyl-2-(methyl-                                        amino)ethyl]-9-propargyl-4,4,5-tripropyl                   702   600           1-[3-(diethylamino)-1,1,2,2-tetraethyl-                                        propyl]-3-ethyl-1-methyl-6-nitro-9-phenethyl               703   601           1-cyclopropyl-1-[1,2-diethyl-3-(diethyl-                                       amino)propyl]-6-methoxy-9-vinyl                            704   602           1,9-dimethyl-1-[4-(methylamino)butyl]                      705   603           9-benzyl-1-[4-(dimethylamino)butyl]-1-                                         methyl                                                     706   604           1,9-diethyl-1-(4-amino-1-methylbutyl)                      707   605           1-[2,3-diethyl-4-(methylamino)butyl]-1,5-                                      dipropyl-3,3,9-trimethyl                                   708   606           1,9-dimethyl-1-[2-(1-pyrrolidinyl)ethyl],                                      nmr (CDCl.sub.3) δ 1.62 (S, 3H), 3.74 (S, 3H),                           m.p. of corresponding hydrochloric acid                                        addition salt, 230 - 231° C.                        709   607           1,9-dimethyl-1-(2-piperidinoethyl),                                            nmr (CDCl.sub.3) δ 1.61 (S, 3H), 2.32 (m, 6H),                           9.81 (m, 2H), m.p. of corresponding                                            hydrochloric acid addition salt, 233 - 235°                             C.                                                         710   608           1,9-dimethyl-1-(2-morpholinoethyl) nmr                                         (CDCl.sub.3) δ 1.62(3H), 2.77(2H), 3.72(3H),                             hydrochloric acid addition salt has                                            m.p. 230 - 231° C.                                  711   609           1,9-dimethyl-1-[2-(4-methyl-1-piperazinyl)-                                    ethyl], nmr (CDCl.sub.3) δ 1.56 (s, 3H),                                 2.22 (S, 3H), 2.3 (m, 8H), dimaleate                                           addition salt has m.p. 194 - 195° C.                712   610           9-ethyl-1-methyl-1-[2-(1-pyrrolidinyl)-                                        ethyl]                                                     713   611           9-ethyl-1-methyl-1-(2-piperidinoethyl)                     714   612           1-methyl-1-(2-morpholinoethyl)-9-propyl                    715   613           1,9-dimethyl-1-{2-[4-(2-hydroxyethyl)-1-                                       piperazinyl]ethyl}, nmr (CDCl.sub.3) δ 1.60                              (s, 3H), 3.70 (s, 3H), m.p. of correspond-                                     ing dihydrochloride salt, m.p. 219 - 220° C.        716   614           1-methyl-9-propyl-1-[3-(1-pyrrolidinyl)-                                       propyl]                                                    717   615           1,9-dimethyl-1-(3-piperidinopropyl)                        718   616           1-methyl-1-(3-morpholinopropyl)-9-phenethyl                719   617           1,9-bis-(3-piperazinopropyl)-1-methyl                      720   618           1-methyl-1-[(1-piperazinyl)methyl]-9-                                          [2-(1-pyrrolidinyl)ethyl]                                  721   619           1-ethyl-9-methyl-1-(2-morpholinoethyl)                     722   620           1,9-diethyl-1-{2-[4-(3-hydroxypropyl)-1-                                       piperazinyl]ethyl-}                                        723   621           9-methyl-1-propyl-1-[2-(1-pyrrolidinyl)-                                       ethyl]                                                     724   622           9-allyl-1(2-morpholinoethyl)-1-propyl                      725   623           9-benzyl-1-isopropyl-1-(2-piperidinoethyl)                 726   624           1,9-dipropyl-3-methyl-1-(2-piperazinoethyl)                727   625           1,9-dimethyl-1-[1-methyl-2-(4-methyl-1-                                        piperazinyl)ethyl]                                         728   626           1-piperazinyl)propyl{1,2-diethyl-3-(4-propyl-                                  1-piperazinyl)propyl}-6-ethoxy-9-(3-                                           piperidinopropyl)                                          729   627           1,9-dimethyl-1-[4-(1-pyrrolidinyl)butyl]                   730   628           9-benzyl-1-{4-[4-(hydroxymethyl)-1-                                            piperazinyl]butyl}-1-methyl                                731   629           7-chloro-4,4-diethyl-1-methyl-1-                                               (4-morpholino-1,1,2,2,3-pentaethylbutyl)-                                      9-vinyl                                                    731a  605a          1-[2-(dimethylamino)ethyl]-1,5,9-trimethyl,                                    nmr (CDCl.sub.3) δ 1.63 (s,3H), 2.20 (s,6H),                             2.67 (s,3H), 3.74 (s,3H), maleate salt                                         has m.p. 144 - 145° C.                              731b  605b          6-benzyloxy-1-[2-(dimethylamino)ethyl]-                                        9-ethyl-1-methyl, nmr (CDCl.sub.3) δ 1.38                                (t, J=7,3H), 1.62 (s,3H), 2.18 (s,6H),                                         hydrochloride salt has m.p. 216 - 217° C.           731c  605c          5-chloro-1-[2-(dimethylamino)ethyl]-1,9-di-                                    methyl, nmr (CDCl.sub.3) δ 1.63 (s,3H), 2.18                             (s,6H), 3.72 (s,3H), maleate salt has                                          m.p. 148 - 151° C.                                  731d  605d          6-benzyloxy-1,9-dimethyl-1-[2-(dimethyl-                                       amino)ethyl], nmr (CDCl.sub.3) δ 1.60 (s,3H),                            2.17 (s,6H), 3.68 (s,3H), 5.12 (s, 2H),                                        hydrochloride salt has m.p. 238 - 239°              __________________________________________________________________________                         C.                                                    

                                      TABLE XVI                                    __________________________________________________________________________          NO. OF THE EXAMPLE                                                             IN WHICH STARTING                                                                             PRODUCT: (PREFIX LISTED BELOW)-1,3,4,9-                    EXAMPLE                                                                             MATERIAL IS PREPARED                                                                          TETRAHYDROTHIOPYRANO[3,4-b]INDOLE                          __________________________________________________________________________     732  630            1,9-dimethyl-1-[2-(dimethylamino)ethyl]                                        nmr (CDCl.sub.3)δ3.72 (s,6H), 6.40 (s,3H); The                           hydrochloric acid addition salt has m.p.                                       254 - 256° C                                        733  631            1,9-dimethyl-1-[2-(methylamino)ethyl]                      734  632            1-(2-aminoethyl)-1,9-dimthyl                               735  633            1,9-dimethyl-1-[2-(hexylamino)ethyl]                       736  634            1-[2-(diethylamino)ethyl]-1,9-dimethyl                     737  635            9-allyl-1-[2-(dimethylamino)ethyl]-1-methyl                                    nmr (CDCl.sub.3)δ 1.79 (s, 3H), 2.18 (s, 6H),                            3.02 (m, 4H), 4.90 (m, 2H), 5.17 (m, 2H),                                      5.95 (m, 1H); corresponding hydrochloric                                       acid addition salt has m.p. 228 - 230° C                                after crystallization from ethanol.                        738  636            1,9-dimethyl-1-[3-(methylamino)propyl]                     739  637            1-[3-(diethylamino)propyl]-1,9-dimethyl                    740  638            9-allyl-1-(3-aminopropyl)-1-methyl                         741  639            9-allyl-1-[3-(dimethylamino)propyl]-1-                                         methyl                                                     742  640            1-methyl-1-[(methylamino)methyl]-9-                                            (3-piperidinopropyl)                                       743  641            1-[(diethylamino)methyl]-6-hydroxy-1-propyl-                                   3,3,9-trimethyl                                            744  642            1-ethyl-9-methyl-1-[2-(methylamino)ethyl]                  745  643            1-[2-(diethylamino)ethyl]-1-ethyl-9-                                           (2-morpholinoethyl)                                        746  644            1-[2-(dimethylamino)ethyl]-1-ethyl-9-β-o-                                 pargyl                                                     747  645            9-methyl-1-[2-(methylamino)ethyl]-1-propyl                 748  646            9-allyl-1-[2-(diethylamino)ethyl]-1-propyl                 749  647            1-cyclohexyl-1-[1,1-dimethyl-2-(methyl-                                        amino)ethyl]-9-propyl                                      750  648            1,9-dimethyl-1-[2-(dimethylamino)ethyl]-                                       6-methoxy                                                  751  649            1-[3-(diethylamino)-1,1,2,2,-tetramethyl-                                      propyl]-3-ethyl-6-nitro-9-vinyl                            752  650            1-cyclopropyl-1-[1,2-diethyl-3-                                                (diethylamino)propyl]-6-ethoxy-9-ethyl                     753  651            1,9-dimethyl-1-[4-(methylamino)butyl]                      754  652            9-allyl-1-[4-(dimethylamino)butyl]-1-                                          methyl                                                     755  653            1-[4-amino-(1-methyllbutyl)-1,9-diethyl]-3-                                    methyl                                                     756  654            9-allyl-1-methyl-1-[2-(1-pyrrolidinyl)-                                        ethyl]                                                     757  655            1,9-dimethyl-1-(2-piperidinoethyl)                         758  656            1-methyl-1,9-bis(2-morpholinoethyl)                        759  657            1-methyl-9-propyl-1-[3-(1-pyrrolidinyl)-                                       propyl]                                                    760  658            1,9-dimethyl-1-(3-piperidinopropyl)                        761  659            1-methyl-1-(3-morpholinopropyl)-9-                                             propargyl                                                  762  660            9-allyl-1-methyl-1-(3-piperazinopropyl)                    763  661            9-allyl-1-methyl-1-[3-(4-methyl-1-                                             piperazinyl)propyl]                                        764  662            1,9-dimethyl-1-[1-pyrrolidinyl)methyl]                     765  663            1-methyl-1-(morpholinomethyl)-9-                                               (3-piperidinopropyl)                                       766  664            1-ethyl-9-methyl-1-(2-morpholinoethyl)                     767  665            1-ethyl-1-{2-[4-(3-hydroxypropyl)-1-                                           piperazinyl]ethyl}-9-propargyl                             768  666            9-methyl-1-propyl-1-[2-(1-pyrrolidinyl)-                                       ethyl]                                                     769  667            1,9-dipropyl-1-(2-morpholinoethyl)                         770  668            1-isopropyl-9-methyl-1-(2-piperidinoethyl)                 771  669            9-benzyl-3-methyl-1-(2-piperazinoethyl)-                                       1-propyl                                                   772  670            1,9-dimethyl-1-[1-methyl-2-(4-methyl-1-                                        piperazinyl)ethyl]                                         773  671            1-cyclopropyl-6-ethoxy-9-ethyl-1-[1,2-                                         diethyl-3-(4-propyl-1-piperazinyl)propyl]                  774  672            1,9-dimethyl-1-[4-(1-pyrrolidinyl)butyl]                   775  673            9-allyl-1-{4-[4-(hydroxymethyl)-1-                                             piperazinyl]butyl}-1-methyl                                __________________________________________________________________________

EXAMPLE 776 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-CARBOXAMIDE (HT: R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O, and Z = CONH₂)

By following the procedure of Example 1 but using boron trifluoride-etherate as the acid catalyst and an equivalent amount of pyruvamide instead of ethyl acetoacetate, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxamide, m.p. 188° - 189° C. after recrystallization from benzene-hexane, identical with the product of Example 133, is obtained.

In the same manner but using an equivalent amount of the appropriate starting material of formula II together with the appropriate α-,β-, γ- or δ- ketoamide, the products listed in Tables III and IV are obtained. For example, by using tryptophol (II; R², R³, R⁴, R⁵, R⁶ = H and X¹ = OH) and the β-ketoamide, N,N-dimethyl-acetoacetamide, in the procedure of this Example, N,N,1-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide, identical with the product of Example 126, is obtained.

EXAMPLE 777 1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-CARBOXYALDEHYDE

A mixture of the starting material, tryptophol (32.2 g, 0.2 mole), acetonyl acetate (23.2 g, 0.2 mole) and 3.2 g of p-toluenesulfonic acid in 50 ml of benzene is refluxed for 1 1/2 hr. in the presence of a Dean-Stark water trap. The benzene solution is washed with 5% sodium bicarbonate, water, dried and evaporated to afford an oil. The oil is subjected to chromatography on a silica gel column using 10% ethyl acetate in benzene as eluent. The acetate 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol acetate is obtained as an oil, nmr (CDCl₃) δ1.52 (S,3H), 2.08(S,3H), 4.35(2H).

This acetate is dissolved in 250 ml of methanol and stirred at room temperature. To this solution is added dropwise 20 ml of 10N NaOH. Hydrolysis is immediate. Most of the methanol is removed under reduced pressure, and water is added. The mixture is rendered neutral and extracted with chloroform. The chloroform extract is dried and evaporated to afford the primary alcohol, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-methanol, m.p. 145° - 147° C., nmr(CDCl₂) δ1.43 (s,3H), 2.68 (t, J = 5.5 cps, 2H), 3.65 (d, J = 6 cps, 2H), 3.86 (t, J = 5.5 cps. 2H), after crystallization from benzene-petroleum ether.

N,N-dicyclohexylcarbodiimide (17.36 g, 0.084 mole) is added to a cooled, stirred solution of the above primary alcohol (6.09 g, 0.028 mole) in 63 ml of dimethyl sulfoxidebenzene (2:1) containing trifluoroacetic acid (1.12 ml, 0.014 mole) and pyridine (2.24 ml, 0.028 mole). The reaction is stirred at room temperature under nitrogen for 5 hr. The reaction mixture is now diluted with 600 ml of ether, followed by the dropwise addition of a solution of oxalic acid (7.56 g) in 21 ml of methanol. After thirty minutes, water (600 ml) is added and the insoluble material is collected. The organic phase is washed with water (2X), 5% aqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO₄) the organic phase is evaporated to yield an oil. the oil is purified by chromatography on silica gel. Elution with 10% ether in benzene affords the title compound as eluate, nmr (CDCl₃) δ1.59 (s,3H H), 2.84 (t, J = 5.5 cps, 2H), 4.15 (t, J = 5.5 cps, 2H).

EXAMPLE 778

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxaldehyde, described in Example 777, is treated with an excess of dimethylamine according to the method of K. N. Campbell, et al., J. Amer. Chem. Soc., 70, 3868 (1948), to yield the corresponding Schiff base. Reduction of the latter compound with sodium borohydride according to the procedure described by E. Schenker, Angew Chem., 73, 81 (1961), affords 1-[(dimethylamino)methyl]-methyl- 1,3,4,9-tetrahydropyrano[3,4-b] indole, identical to the product of Example 317.

By following the procedures of Examples 777 and 778 in sequence, but using as starting material in Example 777 an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, inclusive, and using an equivalent amount of the appropriate ketoalcohol lower alkyl ester of formula VI, described above, and in the procedure of Example 778 using an appropriate amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance, then the respective compounds of formula I, for example, those described in Example 309 (other than the title compound) to 487, inclusive, are obtained.

More specifically exemplified, the use of indole-3-ethanethiol, acetonyl acetate and n-hexylamine in the manner just described for the starting material of formula II, the appropriate ketoalcohol lower alkyl ester and amine, respectively, yields 1-[2-(hexylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole

EXAMPLE 779

Oxidation of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]-indole-1-carboxaldehyde, described in Example 777, with silver oxide according to the method of Delepine and Bonnet, cited above, affords 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-carboxylic acid, nmr (CDCl₃) δ1.79 (s, 3H), 2.83 (t, 2H), 4.17 (t, 2H), 9.20 (1H), identical to the product obtained in Example 4.

By following the procedures of Examples 777 and 779, in sequence, but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, inclusive, instead of tryptophol, and using an equivalent amount of the appropriate ketoalcohol lower alkyl ester of formula VI, in which R¹ is as defined in the first instance and Z is CH₂ OCOR²⁰ or Alk¹ CH₂ OCOR²⁰ wherein R²⁰ and Alk¹ are as defined in the first instance, then the acid compound of formula I in which R⁷ is hydrogen and Y is COOH or Alk¹ COOH wherein Alk¹ is as defined above, for example, the respective products of Examples 1 to 125, inclusive, are obtained.

More specifically exemplified, according to the procedures of Examples 777 and 779 the use of tryptophol and 6-acetoxy-2-hexanone, affords 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-butyric acid, indentical to the product of Example 48. Similarly, the use of tryptophol and 5 -acetoxypentan-2-one affords 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-propionic acid, identical to the product of Example 2.

EXAMPLE 780

1-(AMINOMETHYL)-1-METHYL-1,3,4,9-TETRAHYDROPHYRANO[3,4]INDOLE(I, R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O AND Y = CH₂ NH₂)

A solution of 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b] -indole-1-carboxaldehyde (547 mg), described in Example 777, aqueous hydroxylamine hydrochloride (2.5 ml of 5N) and aqueous sodium acetate (2.5 ml of 5N) and methanol (5 ml) is heated at 50° - 60° C. for 5 min. and then kept at 4° C. for 16 hr. The precipitate is collected and recrystallized from ethanol water to afford 1-methyl-1,3,4,9-tetrahydropyrano [3,4-b]indole-1-carboxaldehyde oxime, m.p. 176° - 178° C.

The latter compound (230 mg) in dry THF (10 ml) is added dropwise to a stirred mixture of lithium aluminum hydride (200 mg) in 15 ml. of THF at ice bath temperature. The mixture is stirred for 1 hr., during which time it is allowed to come to room temperature. Excess lithium aluminum hydride is destroyed by the careful addition of H₂ O/THF(1:1). Insoluble material is collected on a filter and the filtrate is concentrated. The concentrate is taken up in ether. The ether solution is dried (MgSO₄), filtered and concentrated to afford the title compound, identical with the compound of the same name described in Example 316.

EXAMPLE 781 1-METHYL-1-[3-(1-PYRROLIDINYL)PROPYL] -1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE[I, R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O AND ##STR68## ]

To a solution of tryptophol (15 g, 0.09 M) in 150 ml of benzene, 5-chloro-2-pentanone (12 g, 0.10 M) is added. The mixture is heated in the presence of 200 mg of p-toluenesulfonic acid and hydrated alkali-aluminum silicate (Molecular Sieves No. 4). After 1 hr. of refluxing, 400 mg more of acid is added. After a total of 2 hr. the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluent gives 1-(3-chloropropyl)-1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole, nmr (CDCl₃) δ1.33 (3H); 1.93 (4H), 2.75 (2H).

A solution of the latter compound (250 mg, 0.9 millimoles) in 10 ml of THF and 1.5 ml of pyrrolidine is heated at reflux for 16 hr. The mixture is concentrated under reduced pressure and the residue partitioned between 5% sodium carbonate and chloroform. The organic phase is washed with water, dried (Na₂ SO₄), filtered and evaporated under reduced pressure to give the title compound, identical with the product of Example 365.

By following the procedure of Example 781 but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, inclusive, instead of tryptophol, and using an equivalent amount of the appropriate β-, γ-, or δ- haloketone of formula VI, described above, and the appropriate amine of formula HNR⁸ R⁹, described above, then the respective compounds of formula I, for example those described in Examples 309 to 487, inclusive, are obtained.

EXAMPLE 782 1-[(ETHYLAMINO)METHYL]-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE(I, R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O AND Y = CH₂ NHCH₃)

A mixture of tryptophol (3.86 g; II, R², R³, R⁴, R⁵, R⁶ = H and X¹ =OH) and acetamidoacetone (3.0 g), see R. H. Wileg and O.H. Borum, J. Amer. Chem. Soc., 70, 2005 (1948), in 300 ml of dry benzene is stirred and heated to reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is addded and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated. The residue is crystallized from benzene to yield 1-(acetamidomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, m.p. 100° - 102° C. This product is dried under reduced pressure at 27° C. Spectroscopic and analytical data show that the compound is solvated with one mole of benzene which can be removed completely only by melting. R_(f) values of the amide and tryptophol are equal.

The latter product (2.4 g) is dissolved in 80 ml of dry THF and added to a suspension of lithium aluminum hydride in 200 ml of THF.

The resultant slurry is stirred and heated to reflux for 2 hr. cooled and 2.4 g of lithium aluminum hydride is added. The mixture is then refluxed with stirring overnight. The reaction mixture is decomposed with 22.4 ml of water added dropwise over 3 hr. upon stirring and cooling. Stirring is continued for 1 hr. the precipitate is separated by filtration and the filtrate is dried (MgSO₄). Removed of the solvent by evaporation yield the title compound, nmr (DMSO-d₆) δ1.18 (t, 3H), 1.62 (s, 3H), 2.80 (t, 2H), identical to the product of Example 319.

The corresponding hydrochloric acid addition salt, 1-[(ethylamino)methyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, has m.p. 242° - 243° C., after recrystallization from isopropanol-ether.

By following the procedure of Example 782 but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, and using an equivalent amount of an appropriate ketoamide of formula ##STR69## described above, then the respective secondary amine compounds of formula I are obtained.

EXAMPLE 783 1-METHYL-1-NITROMETHYL-1,3,4,9-TETRAHYDROPYRANO-[3,4-b]INDOLE (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O AND Z = CH₂ NO₂)

To a solution of 322 mg of tryptophol (II, R², R³, R⁴, R⁵, R⁶ = H and X¹ = OH) and 248 mg of the nitroketone, nitro-2-propanone, in 100 ml of benzene is added five drops of boron trifluoride etherate and three drops of trifluoracetic acid. The reaction mixture is stirred and heated at reflux under water-separator for 18 hr. The benzene solution is cooled, washed with 10% sodium bicarbonate solution, water, saturated brine solution, and dried over magnesium sulfate. The solvent is removed and the residue is subjected to chromatography on silica gel. Elution with chloroform gives the title compound, γ_(max) ^(CHCl).sbsb.3 3450, 1550cm⁻ ¹, nmr (CDCl₃) δ1.68 (s, 3H), 2.84 (t, 2H), 4.10 (t, 2H).

Reduction of the latter compound with lithium aluminum hydride according to the procedure of Example 309 affords 1-(aminomethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, identical with the product of Example 316.

By following the procedure of Example 783 but using as starting material an equivalent amount of the appropriate starting material of formula II, for example, those described in Examples 1 to 125, and using an equivalent amount of an appropriate nitroketone of formula ##STR70## described above, then the respective primary amine compounds of formula I are obtained.

EXAMPLE 784 6-HYDROXY-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-1-ACETIC ACID(VII; R¹ = CH₃, R², R³, R⁴, R⁵ AND R⁷ = H, R⁶ = 6-OH, X = O, AND Z = CH₂ COOH)

A mixture of 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (5.3 g., 0.015 mole), prepared as described in Example 25, in 250 ml. of anhydrous ethanol, and 1.1 g. of 10% palladium on carbon is stirred at room temperature under a hydrogen atmosphere until no more hydrogen is being taken up by the reaction mixture. The catalyst is removed by filtration through diatomaceous earth (Celite) and the filtrate concentrated. The residue is recrystallized from ethanol-benzene to afford the title compound, m.p. 170° - 171° C.

The corresponding benzylamine salt is prepared by the mixing of equimolar ethereal solutions of benzylamine and the above product. The resulting solid is recrystallized from acetonitrile to afford 6-hydroxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid benzylamine salt, m.p. 191° - 193° C. The corresponding acetate is prepared by allowing a mixture of the title compound and a five molar excess of acetic anhydride in pyridine solution to stand for 24 hr. Dilution of the mixture with water extraction with ether and recrystallization of the extract residue from benzene-petroleum ether, affords 6-acetoxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, identical with the product of Example 24.

By following the procedure of this example but replacing 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid with an equivalent amount of 6-benzyloxy-1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, described in Example 731b, then 1-[2-(dimethylamino)ethyl(]-9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-ol hydrochloride, is obtained m.p. 213° - 214° C; the corresponding free base of the latter compound has pmr (CDCl₃) δ 1.36 (+, j = 7 cps, 3H) 1.6 (s,3H), 2.18 (s,6H). Likewise, replacement with 6-benzyloxy-1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride described in Example 731d, gives 1,9-dimethyl-1 -[2-(dimethylamino)ethyl]1,3,4,9-tetrahydropyrano[3,4-b]indol-6-ol hydrochloride, m.p. 242° -244° C., corresponding free base has nmr (CDCl₃) δ 1.6 (s,3H), 2.2 (s, 6H), 3.7 (s,3H).

EXAMPLE 785 1,1-DIMETHYL-1,3,4,9-TETRAHYDROPYRANO-[3,4-b]INDOLE (VII; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶, AND R⁷ = H AND Z = CH₃)

A solution of tryptophol (8 g, 0.05M), acetone (5 g) and p-toluenesulfonic acid (100 mg) in 100 ml of benzene containing hydrated alkali-aluminium silicate (Molecular Sieves No. 4) is heated to reflux for 1 hr. More p-toluenesulfonic acid (100 mg) and the ketone, acetone (3 g), is added and the reflux continued for a further 1.5 hr.

The mixture is filtered and the filtrate is washed with 5% sodium bicarbonate and water. After drying over sodium sulfate the benzene is evaporated under reduced pressure affording a solid. Chromatography of this solid on silica gel using 30% ethyl acetate in benzene as eluant gives a white product which is recrystallized once from benzene-petroleum ether to give the title compound, m.p. 142° - 144° C., nmr (CDCl₃) δ2.76 (t, J = 5.5 cps, 2H), 4.03 (t, J = 5.5 cps, 2H).

The procedure of Example 785 is followed to prepare other compounds of formula VII in which R¹, R², R³, R⁴, R⁵, R⁶ are as defined in the first instance, R⁷ is hydrogen and Z is lower alkyl or phenyl(lower)alkyl. Examples of such compounds are listed in Tables XVII and XVIII. In each example an equivalent amount of the starting material of formula II listed therein is used instead of the starting material of formula II described in Example 785, together with the appropriate ketone.

                                      TABLE XVII                                   __________________________________________________________________________      EXAMPLE                                                                              STARTING MATERIAL OF FORMULA II                                                                        ##STR71##                                                                                   ##STR72##                          __________________________________________________________________________           R.sup.2                                                                            R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                              X R.sup.1                                                                             Z                                           786   H   H   H   H   H     O C.sub.2 H.sub.5                                                                     n-C.sub.3 H.sub.7                                                                      1-ethyl-1-propyl                    787   H   H   H   H   H     O CH.sub.3                                                                            n-C.sub.3 H.sub.7                                                                      1-methyl-1-propyl, m.p.                                                        91-93° C.                    788   H   H   H   H   H     O C.sub.2 H.sub.5                                                                      ##STR73##                                                                             1-ethyl-1-phenethyl                 789   H   H   H   H   H     O CH.sub.3                                                                             ##STR74##                                                                             1-benzyl-1-methyl, m.p. 141-                                                   145° C.                      790   CH.sub.3                                                                           H   H   H   H     O CH.sub.3                                                                            CH.sub.3                                                                               1,1,3-trimethyl                     791   n-C.sub.3 H.sub.7                                                                  H   H   H   H     O CH.sub.3                                                                            n-C.sub.3 H.sub.7                                                                      1,3-dipropyl-1-methyl               792   CH.sub.3                                                                           CH.sub.3                                                                           H   H   H     O                                                                                 ##STR75##                                                                          CH.sub.3                                                                               1-cyclopropyl-1,3,3-tri-                                                       methyl                              793   C.sub.2 H.sub.5                                                                    H   C.sub.2 H.sub.5                                                                    H   H     O                                                                                 ##STR76##                                                                          n-C.sub.3 H.sub.7                                                                      1-cyclohexyl-3,4-diethyl-                                                      1-propyl                            794   H   H   CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                  H     O CH.sub.3                                                                            n-C.sub.3 H.sub.7                                                                      1,4-dimethyl-1,4-dipropyl           795   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           H     O CH.sub.3                                                                             ##STR77##                                                                             1-benzyl-1,3,3,4,4-penta-                                                      methyl                              796   H   H   H   H   4-CH.sub.3                                                                           O                                                                                 ##STR78##                                                                          CH.sub.3                                                                               1-cyclopropyl-1,5-dimethyl          797   H   H   H   H   5-C.sub.2 H.sub.5                                                                    O                                                                                 ##STR79##   1-cyclopentyl-6-ethyl               798   C.sub.2 H.sub.5                                                                    H   H   H   6-OCH.sub.3                                                                          O C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                        7-methoxy-1,1,3-triethyl            799   CH.sub.3                                                                           CH.sub.3                                                                           H   H   7-OCH.sub.2 H.sub.5                                                                  O CH.sub.3                                                                            CH.sub.3                                                                               8-ethoxy-1,1,3,3-tetra-                                                        methyl                              800   C.sub.2 H.sub.5                                                                    H   H   H   5-NO.sub.2                                                                           O C.sub.2 H.sub.5                                                                      ##STR80##                                                                             1,3-diethyl-6-nitro- 1-(3-pheny                                                lpropyl)                            801   H   H   H   H   7-NO.sub.2                                                                           O CH.sub.3                                                                            CH.sub.3                                                                               1,1-dimethyl-8-nitro                802   H   H   H   CH.sub.3                                                                           6-CH.sub.3 COO                                                                       O C.sub.2 H.sub.5                                                                     CH.sub.3                                                                               7-acetoxy-1,4-dimethyl-                                                        1-ethyl                             803   n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  H   H   5-C.sub.2 H.sub.5 COO                                                                O                                                                                 ##STR81##                                                                           ##STR82##                                                                             1-benzyl-1-cyclopropyl-                                                        3,3-dipropyl-6-propionyl- oxy       804   H   H   H   H   4-Cl  O                                                                                 ##STR83##                                                                          CH.sub.3                                                                               5-chloro-1-cyclopropyl-                                                        methyl                              805   CH.sub.3                                                                           H   H   H   6-Cl  O                                                                                 ##STR84##                                                                           ##STR85##                                                                             1-benzyl-7-chloro- 1-cyclohexyl                                                -3-methyl                           806   C.sub.2 H.sub.5                                                                    H   H   H   5-Br  O C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                        6-bromo-1,1,3-triethyl              807   H   H   n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  7-Br  O n-C.sub.3 H.sub.7                                                                   CH.sub.3                                                                               8-bromo-1-methyl-1,4,4-                                                        tripropyl                           808   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           4-F   O CH.sub.3                                                                            CH.sub.3                                                                               5-fluoro-1,1,3,3,4,4-                                                          hexamethyl                          809   H   H   H   H   6-F   O                                                                                 ##STR86##                                                                          n-C.sub.3 H.sub.7                                                                      1-cyclopropyl-7-fluoro-                                                        1-propyl                            810   CH.sub.3                                                                           H   CH.sub.3                                                                           H   7-I   O CH.sub.3                                                                             ##STR87##                                                                             8-iodo-1-phenethyl- 1,3,4-trime                                                thyl                                811   H   H   H   H   5-I   O CH.sub.3                                                                            CH.sub.3                                                                               1,1-dimethyl-6-iodo                 __________________________________________________________________________

                                      TABLE XVIII                                  __________________________________________________________________________      EX.                                                                               STARTING MATERIAL OF FORMULA II                                                                        ##STR88##  PRODUCT: (PREFIX LISTED                                                        BELOW)-1,3,4,9- TETRAHYDROTHIOPYRAN                                            O- [3,4-b]INDOLE                        __________________________________________________________________________        R.sup.2                                                                            R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                            R.sup.6                                                                              X R.sup.1                                                                            Z                                               812                                                                               H   H   H   H   H     S CH.sub.3                                                                           CH.sub.3                                                                               1,1-dimethyl                            813                                                                               H   H   H   H   H     S CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                      1-methyl-1-propyl                       814                                                                               H   H   H   H   H     S C.sub.2 H.sub.5                                                                     ##STR89##                                                                             1-ethyl-1-phenethyl                     815                                                                               H   H   H   H   H     S CH.sub.3                                                                            ##STR90##                                                                             1-benzyl-1-methyl                       816                                                                               CH.sub.3                                                                           H   H   H   H     S CH.sub.3                                                                           CH.sub.3                                                                               1,1,3-trimethyl                         817                                                                               n-C.sub.3 H.sub.7                                                                  H   H   H   H     S CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                      1,3-dipropyl-1-methyl                   818                                                                               CH.sub.3                                                                           H   H   H   H     S                                                                                 ##STR91##                                                                         n-C.sub.3 H.sub.7                                                                      1-cyclohexyl-3,4-diethyl- 1-propyl      820                                                                               H   H   CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                  H     S CH.sub.3                                                                           n-C.sub.3 H.sub.7                                                                      1,4-dimethyl-1,4-dipropyl               821                                                                               CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           H     S CH.sub.3                                                                            ##STR92##                                                                             1-benzylmethyl-1,3,3,4- 4-pentameth                                            yl                                      822                                                                               H   H   H   H   4-CH.sub.3                                                                           S                                                                                 ##STR93##                                                                         CH.sub.3                                                                               1-cyclopropyl-1,5- dimethyl             823                                                                               H   H   H   H   5-C.sub.2 H.sub.5                                                                    S                                                                                 ##STR94##  1-cyclopentyl-6-ethyl                   824                                                                               C.sub.2 H.sub.5                                                                    H   H   H   6-OCH.sub.3                                                                          S C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                        7-methoxy-1,1,3-triethyl                825                                                                               CH.sub.3                                                                           CH.sub.3                                                                           H   H   7-OC.sub.2 H.sub.5                                                                   S CH.sub.3                                                                           CH.sub.3                                                                               8-ethoxy-1,1,3,3-                                                              tetramethyl                             826                                                                               C.sub.2 H.sub.5                                                                    H   H   H   5-NO.sub.2                                                                           S C.sub.2 H.sub.5                                                                     ##STR95##                                                                             1,3-diethyl-6-nitro- 1-(3-phenylpro                                            pyl)                                    827                                                                               H   H   H   H   7-NO.sub.2                                                                           S CH.sub.3                                                                           CH.sub.3                                                                               1,1-dimethyl-8-nitro                    828                                                                               H   H   H   CH.sub.3                                                                           6-CH.sub.3 COO                                                                       S C.sub.2 H.sub.5                                                                    CH.sub.3                                                                               7-acetoxy-1,4-dimethyl-                                                        1-ethyl                                 829                                                                               n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  H   H   5-C.sub.2 H.sub.5 COO                                                                S                                                                                 ##STR96##                                                                          ##STR97##                                                                             1-benzyl-1-cyclopropyl- 3,3-dipropy                                            l-6- propionyloxy                       830                                                                               H   H   H   H   4-Cl  S                                                                                 ##STR98##                                                                         CH.sub.3                                                                               5-chloro-1-cyclopropyl-1- methyl        831                                                                               CH.sub.3                                                                           H   H   H   6-Cl  S                                                                                 ##STR99##                                                                          ##STR100##                                                                            1-benzyl-7-chloro-1- cyclohexyl-3-m                                            ethyl                                   832                                                                               C.sub.2 H.sub.5                                                                    H   H   H   5-Br  S C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                        6-bromo-1,1,3-triethyl                  833                                                                               H   H   n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  7-Br  S n-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                               8-bromo-1-methyl-1,4,4-                                                        tripropyl                               834                                                                               CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           4-F   S CH.sub.3                                                                           CH.sub.3                                                                               5-fluoro-1,1,3,3,4,4-                                                          hexamethyl                              835                                                                               H   H   H   H   6-F   S                                                                                 ##STR101##                                                                        n-C.sub.3 H.sub.7                                                                      1-cyclopropyl-7-fluoro- 1-propyl        836                                                                               CH.sub.3                                                                           H   CH.sub.3                                                                           H   7-I   S CH.sub.3                                                                            ##STR102##                                                                            8-iodo-1-phenethyl- 1,3,4-trimethyl                                            O                                       837                                                                               H   H   H   H   5-I   S CH.sub.3                                                                           CH.sub.3                                                                               1,1-dimethyl-6-iodo                     __________________________________________________________________________

EXAMPLE 838 1,1-DIMETHYL-9-[2-(DIMETHYLAMINO)ETHYL]-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE (I; R¹ AND Y = CH₃, R², R³, R⁴, R⁵ AND R⁶ = H, AND R⁷ = CH₂ CH₂ N(CH₃)₂ ]

To 4.2 g. of a 50% dispersion of sodium hydride in 20 ml. of dimethylformamide is added a solution of 7 g. of 1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole, described in Example 785, in 20 ml. of dimethylformamide. The addition is made dropwise at room temperature while stirring vigorously. The mixture is heated for 1 hr. at 40° C. Then an excess of the organic halide, dimethylaminoethyl chloride (free base obtained from 15 g. of the hydrochloride) is added and stirring continued at 40° C. overnight.

The reaction mixture is poured into ice-water, acidified with 6NHCl and washed with ether. The aqueous phase is rendered alkaline with 10% NaOH and extracted with benzene. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to yield the title compound, nmr (CDCl₃) δ1.63 (6H), 2.36 (6H), 2.79 (m, 4H), 4.10 (m, 4H), 7.18 (m, 4H).

The corresponding hydrochloric acid addition salt, 1,1-dimethyl-9-[(2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride, has m.p. 198° - 200° C., after crystallization from methanol-ether.

The procedure of Example 838 is followed to prepare other compounds of formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and X are as defined in the first instance, R⁷ is aminoalkyl as defined above and Y is lower alkyl or phenyl(lower)alkyl. Examples of such compounds are listed in Tables XIX and XX. In each example an equivalent amount of the appropriate starting material of formula VII in which R¹, R², R³, R⁴, R⁵, R⁶ are as defined in the first instance, R⁷ is hydrogen and Z is lower alkyl or phenyl(lower)alkyl, described in Examples 785 to 837, is used in place of 1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole if required. In each case the starting material of formula VII is noted by the example in which it is prepared.

                                      TABLE XIX                                    __________________________________________________________________________           NO. OF THE                                                                     EXAMPLE IN                                                                     WHICH STARTING           PRODUCT: (PREFIX LISTED BELOW)-                       MATERIAL IS                                                                              ORGANIC        1,3,4,9-TETRAHYDROPYRANO-                       EXAMPLE                                                                              PREPARED  HALIDE         [3,4,-b]INDOLE                                  __________________________________________________________________________     839   785       (CH.sub.3).sub.2 N(CH.sub.2).sub.3 Cl                                                         1,1-dimethyl-9-[3-(dimethyl-                                                   amino)propyl], nmr (CDCl.sub.3)                                                δ1.62 (6H), 2.00 (m, 2H), 2.25                                           (6H), corresponding hydrochloric                                               acid additionn salt has m.p.                                                   201 - 203° C.                            840   785       CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                                1,1-dimethyl-9-[2-(methylamino)-                                               ethyl]                                          841   785       i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                       1,1,-dimethyl-9-[2-(isopropyl-                                                 amino)ethyl]                                    842   786       NH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 Br                                               9-(3-amino-2,2-dimethylethyl)-                                                 1-ethyl-1-propyl                                843   787       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         9-[2-(dimethylamino)ethyl]-1-                                                   ##STR103##                                                                    1470, 1085 cm.sup..sup.-1, maleate salt                                        has m.p. 144 - 147° C.                   844   788       C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                         1-ethyl-9-[3-(ethylamino)propyl]-                                              1-phenethyl                                     845   789       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-benzyl-9-[2-(dimethylamino)-                                                 ethyl]-1-methyl, nmr (CDCl.sub.3)                                              δ1.55 (s, 3H), 2.92 (6H), 3,95                                           (2H), corresponding hydrochloric                                               acid addition salt has m.p.                                                    218 - 220° C.                            846   789       CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                                1-benzyl-1-methyl-9-[2-(methyl-                                                amino)ethyl]                                    847   789       NH.sub.2 (CH.sub.2).sub.3 Cl                                                                  9-(4-aminobutyl)-1-benzyl-1-                                                   methyl                                          848   790       (CH.sub.3).sub.2 NCH.sub.2 [CH(CH.sub.3)].sub.2 Cl                                            9-[1,2-dimethyl-3-(dimethyl-                                                   amino)propyl]-1,1,3-trimethyl                   849   791       (C.sub.2 H.sub.5).sub.2 NCH(C.sub.2 H.sub.5)CH.sub.2                                          9-[2-(diethylamino)-2-                                                         ethylethyl]-1,3-dipropyl-1-                                                    methyl                                          850   792       CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                                1-cyclopropyl-9-[3-(methyl-                                                    amino)propyl]-1,3,3-trimethyl                   851   793       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-cyclohexyl-3,4-diethyl-                                                      9-[2-(dimethylamino)ethyl]-                                                    1-propyl                                        852   794       (n-C.sub.3 H.sub.7).sub.2 N(CH.sub.2).sub.3 Cl                                                1,4-dimethyl-1,4-dipropyl-9-                                                   [3-(dipropylamino)propyl]                       853   795       (CH.sub.3).sub.2 NCH(n-C.sub.3 H.sub.7)CH.sub.2 Cl                                            1-benzyl-9-[2-(dimethylamino)-                                                 2-propylethyl]-1,3,3,4,4-                                                      pentamethyl                                     854   796       (CH.sub.3).sub.2 N[CH(n-C.sub.3 H.sub.7)] .sub.3 CH.sub.2                      Cl             1-cyclopropyl-1,5-dimethyl-9-                                                  [4-(dimethylamino)-2,3,4-                                                      tripropylbutyl]                                 855   797       (C.sub.2 H.sub.5).sub.2 N(CH.sub.2) .sub.2 Cl                                                 1-cyclopentyl-9-[2-(diethyl-                                                   amino)ethyl]-6-ethyl                            856   798       CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                                7-methoxy-9-[3-(methylamino)-                                                  propyl]-1,1,3-triethyl                          857   799       n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                       8-ethoxy-9-[2-(propylamino)-                                                   ethyl]-1,1,3,3-tetramethyl                      858   800       i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                       1,3-diethyl-9-[2-(isopropyl-                                                   amino)ethyl]-6-nitro-1-                                                        (3-phenylpropyl)                                859   801       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1,1-dimethyl-9-[2-(dimethyl-                                                   amino)ethyl]-8-nitro                            860   802       C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                         7-acetoxy-1,4-dimethyl-1-ethyl-                                                9-[3-(ethylamino)propyl]                        861   803       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                         1-benzyl-1-cyclopropyl-9-[2-                                                   (dimethylamino)ethyl-3,3-                                                      dipropyl-6-propionyloxy]                        862   804       n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.3 Cl                                                       5-chloro-l-cyclopropyl-1-                                                      methyl-9-[3-(propylamino)-                                                     propyl]                                         863   805       1-(3-chloropropyl)-                                                                           1-benzyl-7-chloro-1-cyclohexyl-                                 pyrrolidine    3-methyl-9-[3-(1-pyrrolidinyl)-                                                propyl]                                         864   806       1-(2-chloroethyl)-                                                                            6-bromo-9-(2-piperidinoethyl)-                                  piperidine     1,1,3-triethyl                                  865   807       4-(2-chloroethyl)-                                                                            8-bromo-1-methyl-9-(2-morpholino-                               morpoline      ethyl)-1,4,4-tripropyl                          866   808       1-(3-chloropropyl)-                                                                           5-fluoro-1,1,3,3,4,4-hexamethyl-                                piperazine     9-(piperazinopropyl)                            867   809       1-(3-chloroethyl)-4-                                                                          1-cyclopropyl-7-fluroro-9-                                      methylpiperazine                                                                              [2-(4-methyl-1-piperazinyl)-                                                   ethyl]-1-propyl                                 868   810       1-(2-chloroethyl)-4-                                                                          9-}2-[4-(hydroxyethyl)-1-                                       (hydroxyethyl)piperazine                                                                      piperazinyl]ethyl}-8-iodo-1-                                                   phenyethyl-1,3,4-trimethyl                      869   811       1-(2-chloroethyl)-                                                                            1,1-dimethyl-6-iodo-9-[2-(1-                                    pyrrolidine    pyrrolidinyl)ethyl]                             870   785       1-(3-chloropropyl)-                                                                           1,1-dimethyl-9-(3-piperidino-                                   piperidine     propyl)                                         871   785       4-(4-chlorobutyl)-                                                                            1,1-dimethyl-9-(4-morpholino-                                   morpholine     butyl)                                          872   789       1-(4-chlorobutyl)-                                                                            9-[4-(4-methyl-1-piperazinyl)-                                  4-methylpiperazine                                                                            butyl]                                          873   789       1-(2-chloroethyl)-4-                                                                          1-benzyl-9-{2-[4-(hydroxypropyl)-                               (3-hydroxypropyl)-                                                                            1-piperazinyl]ethyl}-1-methyl                                   piperazine                                                     __________________________________________________________________________

                                      TABLE XX                                     __________________________________________________________________________           NO. OF                                                                         EXAMPLE IN                                                                     WHICH STARTING          PRODUCT:                                               MATERIAL IS                                                                               ORGANIC      (PREFIX LISTED BELOW)-1,3,4,9-                   EXAMPLE                                                                              PREPARED   HALIDE       TETRAHYDROTHIOPYRANO[3,4-b]INDOLE                __________________________________________________________________________     874   812       (CH.sub.3).sub.2 N(CH.sub.2).sub.3 Cl                                                        1,1-dimethyl-9-[3-(dimethyl-                                                   amino)propyl]                                    875   812       CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                               1,1-dimethyl-9-[2-(methylamino)-                                               ethyl]                                           876   812       i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      1,1-dimethyl-9-[2-(isopropyl-                                                  amino)ethyl]                                     877   812       NH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 Br                                              9-(3-amino-2,2-dimethylethyl)-                                                 1,1-dimethyl                                     878   813       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        9-[2-(dimethylamino)ethyl]-                                                    1-methyl-1-propyl                                879   814       C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                        1-ethyl-9-[ 3-(ethylamino)propyl]-                                             1-phenethyl                                      880   815       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-benzyl-9-[2-(dimethylamino)-                                                 ethyl]-1-methyl                                  881   815       CH.sub.3 NH(CH.sub.2).sub.2 Cl                                                               1-benzyl-1-methyl-9-[2-(methyl-                                                amino)ethyl]                                     882   815       NH.sub.2 (CH.sub.2).sub.3 Cl                                                                 9-(4-aminobutyl)-1-benzyl-1-                                                   methyl                                           883   816       (CH.sub.3).sub.2 NCH.sub.2 [CH(CH.sub.3)].sub.2 Cl                                           9-[1,2-dimethyl-3-(dimethyl-                                                   amino)propyl]-1,1,3-trimethyl                    884   817       (C.sub.2 H.sub.5).sub.2 NCH(C.sub.2 H.sub.5)CH.sub.2                                         9-[2-(diethylamino)-2-ethyl-                                                   ethyl]-1,3-dipropyl-1-methyl                     885   818       CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                               1-cyclopropyl-9-[3-(methyl-                                                    amino)propyl]-1,3,3-trimethyl                    886   819       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-cyclohexyl-3,4-diethyl-9-                                                    [2-(dimethylamino)ethyl]-1-                                                    propyl                                           887   820       (n-C.sub.3 H.sub.7).sub.2 N(CH.sub.2).sub.3 Cl                                               1,4-dimethyl-1,4-dipropyl]-9-                                                  [3-(dipropylamino)propyl]                        888   821       (CH.sub.3).sub.2 NCH(n-C.sub.3 H.sub.7)CH.sub.2 Cl                                           1-benzyl-9-[2-(dimethylamino)-                                                 2-propylethyl]-1,3,3,4,4-                                                      pentamethyl                                      889   822       (CH.sub.3).sub.2 N[CH(n-C.sub.3 H.sub.7)].sub.3 CH.sub.2                       Cl            1-cyclopropyl-1,5-dimethyl-9-                                                  [4-(dimethylamino)-2,3,4-                                                      tripropylbutyl]                                  890   823       (C.sub.2 H.sub.5).sub.2 N(CH.sub.2).sub.2 Cl                                                 1-cyclopentyl-9-[2-(diethyl-                                                   amino)ethyl]-6-ethyl                             891   824       CH.sub.3 NH(CH.sub.2).sub.3 Cl                                                               7-methoxy-9-[3-(methylamino)-                                                  propyl]-1,1,3-triethyl                           892   825       n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      8-ethoxy-9-[2-(propylamino)-                                                   ethyl]-1,1,3,3-tetramethyl                       893   826       i-C.sub.3 H.sub.7 NH(CH.sub.2).sub.2 Cl                                                      1,3-diethyl-9-[2-(isopropyl-                                                   amino)ethyl]-6-nitro-1-(3-                                                     phenylpropyl)                                    894   827       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1,1-dimethyl-9-[2-(dimethyl-                                                   amino)ethyl]-8-nitro                             895   828       C.sub.2 H.sub.5 NH(CH.sub.2).sub.3 Cl                                                        7-acetoxy-1,4-dimethyl-1-                                                      ethyl-9-[3-(ethylamino)propyl]                   896   829       (CH.sub.3).sub.2 N(CH.sub.2).sub.2 Cl                                                        1-benzyl-1-cyclopropyl-9-                                                      [2-(dimethylamino)ethyl]-3,3-                                                  dipropyl-6-propionyloxy                          897   830       n-C.sub.3 H.sub.7 NH(CH.sub.2).sub.3 Cl                                                      5-chloro-1-cyclopropyl-1-methyl-                                               9-[3-(propylamino)propyl]                        898   831       1-(3-chloropropyl)-                                                                          1-benzyl-7-chloro-1-cyclohexyl-                                  pyrrolidine   3-methyl-9-[3-(1-pyrrolidinyl)-                                                propyl]                                          899   832       1-(2-chloroethyl)-                                                                           6-bromo-9-(2-piperidinoethyl)-                                   piperidine    1,1,3-triethyl                                   900   833       4-(2-chloroethyl)-                                                                           8-bromo-1-methyl-9-(2-morpholine-                                morpholine    ethyl)-1,4,4-tripropyl                           901   834       1-(3-chloropropyl)-                                                                          5-fluoro-1,1,3,3,4,4-hexamethyl-                                 piperazine    9-(piperazinopropyl)                             902   835       1-(3-chloroethyl)-                                                                           1-cyclopropyl-7-fluoro-9-                                        4-methylpiperazine                                                                           [2-(4-methyl-1-piperazinyl)-                                                   ethyl]-1-propyl                                  903   836       1-(2-chloroethyl)-                                                                           9-{2-[4-(hydroxyethyl)-1-                                        4-(hydroxyethyl)-                                                                            piperazinyl]ethyl}-8-iodo-                                       piperazine    1-phenethyl-1,3,4-trimethyl                      904   837       1-(2-chloroethyl)-                                                                           1,1-dimethyl-6-iodo-9-[2-(1-                                     pyrrolidine   pyrrolidinyl)ethyl]                              905   812       1-(3-chloropropyl)-                                                                          1,1-dimethyl-9-(3-piperidine-                                    piperidine    propyl)                                          906   812       4-(4-chlorobutyl)-                                                                           1,1-dimethyl-9-(4-morpholino-                                    morpholine    butyl)                                           907   815       1-(4-chlorobutyl)-                                                                           1-benzyl-1-methyl-9-[4-(4-                                       4-methylpiperazine                                                                           methyl-1-piperazinyl)butyl]                      908   815       1-(2-chloroethyl)-                                                                           1-benzyl-9-{2-[4-(hydroxypropyl)-                                4-(3-hydroxypropyl)-                                                                         1-piperazinyl]ethyl}-1-methyl                                    piperazine                                                     __________________________________________________________________________

EXAMPLE 909 1,1-DIMETHYL-9-[2-(DIMETHYLAMINO)ETHYL]-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE-6-OL [I, R¹ AND Y = CH₃, R², R³, R⁴ AND R⁵ = H, R⁶ = OH and R⁷ = CH₂ CH₂ N(CH₃)₂ ]

5-Benzyloxy-3-tryptophol (II; R², R³, R⁴ and R⁵ = H, R⁶ = 5-benzyloxy and X¹ = OH), m.p. 93° - 95° C., is prepared by lithium aluminum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Patent 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VII; R¹ M CH₃), nmr (CDCl₃) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67 - 7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyll chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.

The latter compound, 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrochloride (11.5 g., 0.028M) in 600 ml. of absolute ethanol and 600 mg of 10% palladium on carbon is stirred at room temperature under a hydrogen atmosphere for 22 hr. until no more hydrogen is taken up by the reaction. The catalyst is collected on celite and the filtrate concentrated to afford the corresponding hydrochloride acid addition salt of the title compound, m.p. 225° - 228° C., after recrystallization from ethanol-ether.

The title compound [free base, nmr (CDCl₃) δ1.61 (6H), 2.57 (t, J = 5 cps, 2h), 3.86 (t, J = 5 cps, 2H)]is obtained by decomposing the hydrochloric acid addition salt, for example, by washing a chloroform solution of the salt with 10% sodium hydroxide solution and evaporating the solvent.

By replacing 5-benzyloxy-3-tryptophol with an equivalent amount of 7-benzyloxy-3-tryptophol in the procedure of this example, 1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole-8-ol is obtained.

EXAMPLE 910 1-(2-AMINOETHYL)-1-METHYL-1,3,4,9-TETRAHYDROPYRANO[3,4-b]INDOLE (I; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ AND R⁷ = H, X = O AND Y = CH₂ NH₂)

1-Methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (20.0 g., 0.817 mole), described in Example 126, is dissolved in dry methylene chloride (400 ml) and freshly prepared triethyloxonium fluoroborate (17.00 g., 0.894 mole) is added in one portion to the solution. The reaction mixture is stirred at room temperature for 2 hr.. The methylene chloride solution is washed with cold 30% aqueous potassium carbonate followed by brine and the dried organic layer is concentrated under reduced pressure. The residue is dissolved in ether (150 ml.). The solution is filtered and crystallization proceeds at room temperature to afford ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetimidate, m.p. 139.5° - 141° C.

The latter compound (4.79 g., 0.0176 mole) dissolved in dry THF (100 ml.) is added dropwise to a stirred and icecooled suspension of lithium aluminum hydride (1.75 g., 0.046 mole) in THF (50 ml.). The reaction mixture is stirred overnight at room temperature and then dilute sodium hydroxide is added dropwise to decompose excess hydride. The precipitate is collected by filtration and the filtrate is concentrated under reduced pressure thus affording a residue which is extracted with methylene chloride. The organic layers are washed with brine, dried (MgSO₄) and concentration of the solvent and crystallization from ether affords the title compound, m.p. 80° - 84° C., γ_(max) ^(CHCl).sbsb.3 3455, 3280 cm.sup.⁻¹, identical with the compound of the same name described in Example 309.

EXAMPLE 911 1-[ 2-(DIMETHYLAMINO)ETHYL]-9-ETHYL-1-METHYL-1,3,4,9-TETRAHYDROTHIOPYRANO[3,4-b]INDOLE [I; R¹ = CH₃, R², R³, R⁴, R⁵, AND R⁶ = H,R.sup. 7 = C₂ H₅, X = S AND Y = CH₂ CH₂ N(CH₃)₂ ]

The compound of formula I in which R⁷ = H and Y = amino(lower)alkyl,1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole (822 mg), described in Example 398, is dissolved in 15 ml of DMF and 15 ml of benzene. To remove all possible traces of water, a portion of this benzene is distilled. After cooling to 0° C, 140 mg of sodium hydride (54% suspension in mineral oil) is added, and the mixture stirred for 15 min. Alkylation is accomplished by addition of 350 mg of ethyl bromide and stirring the reaction mixture at 0° C for 20 min. The resulting suspension is poured onto cracked ice, extracted with chloroform, the organic layer washed repeatedly with water and evaporated. Chromatography of the residue on silica gel (20 g) using chloroform-methanol (0-10%) affords the title compound, which after crystallization from ether hexane has m.p. 86° - 88° C., γ_(max) ^(CHCl).sbsb.3 2820, 2765, 1600, 1568, 1537 cm.sup.⁻¹, nmr (CDCl₃) δ2.20 (s, 6H), 2.30 (m, 4H).

The corresponding hydrochloric acid addition salt of the title compound, 1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole hydrochloride, has m.p. 220° - 222° C.

By following the procedure of Example 911 and using an appropriate compound of formula I in which R⁷ is hydrogen and Y is an amino(lower)alkyl, for instance those described in Examples 309 to 487, together with the appropriate organic halide, then other compounds of formula I in which R⁷ is lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or amino(lower)alkyl are obtained.

For example, the use of the same compound of formula I as described in Example 911 with an equivalent amount of methyl bromide, instead of ethyl bromide, in the procedure of Example 911 gives 1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9tetrahydrothiopyrano[3,4-b]indole, nmr (CDCl₃) δ 3.72 (s, 6H), 6.40 (s, 3H), identical to the product of Example 732. The corresponding hydrochloric acid addition salt of this latter compound, 1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole hydrochloride has m.p. 244° - 246° C.

Likewise, the use of the same compound of formula I as described in Example 911 with an equivalent amount of propyl bromide, instead of ethyl bromide, gives 1-[2-(dimethylamino)-ethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, nmr(CDCl₃) δ 1.03(t, 3H), 1,83(S,3H), 2.22(S,6H), 4.14(m, 2H), 7.22(m, 4H; corresponding hydrochloric acid addition salt has m.p. 243°-245° C.

EXAMPLE 912 1-[(2-Dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydropyrano[3,4b]indole [1; R¹ = CH₃, R², R³, R⁴, R⁵, R⁶ and R⁷ = H, X = O and Y = CH₂ CH₂ (N(CH₃)₂ ]

To a solution of p-toluenesulfonic acid (2.28 g) in toluene (40 ml), the starting material of formula II, tryptophol (1.61 g), and the aminoketone, 4-(dimethylamino)-2-butanone (1.27 g) are added. The mixture is evaporated under reduced pressure and the residue stirred under nitrogen at 130° C (bath temperature) for 45 min.. The mixture is cooled, water (20 ml) added and the mixture extracted with toluene. The toluene extract is washed with 5% sulfuric acid (5ml) and with water (5 ml). The aqueous layer containing a dark heavy oil is combined with the aqueous washes. Conc. NH₄ OH (10 ml) is added and the mixture extracted with toluene (10 ml and 2 × 5 ml). The combined toluene solution is washed with water (2 × 5 ml), dried (Na₂ SO₄), treated with charcoal and evaporated under reduced pressure. The residue is recrystallized from ether to afford the pure title compound, identical to the product of the same name described in Example 309.

EXAMPLE 913 1,9-Dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole [1; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵, and R⁶ = H, X = O and Y = CH₂ CH₂ N(CH₃)₂ ]

To a mixture of the starting material of formula II, N-methyltryptophol (0.50 g), and the aminoketone, 4-dimethylamino-2-butanone (0.363 g), p-toluenesulfonic acid (0.650 g) is added in portions and the mixture stirred under nitrogen at 130° C for 11/2 hr. After cooling water is added (10 ml) and the mixture is extracted with toluene (2 × 5 ml). The combined toluene solution is backwashed with water and discarded. The aqueous phase, containing a heavy brown oil, is made alkaline with conc. ammonium hydroxide (10 ml) and extracted with benzene (3 × 10 ml). The combined benzene extract is washed with water (2 × 10 ml), dried (Na₂ SO₄), treated with charcoal and evaporated under reduced pressure to yield the title compound, identical to the product of the same name described in Example 674.

EXAMPLE 914 1,9-Dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole [1; R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X = S and Y = CH₂ CH₂ N(CH₃)₂ ]

A mixture of the starting material of formula II, 1-methylindole-3-ethanethiol (0.75 g), 4-dimethyl-amino-2-butanone hydrochloride (0.72 g), toluene (ca. 1 ml) and p-toluenesulfonic acid (1.00 g), is stirred under nitrogen at 125° C for 1/2 hr. After cooling, water (20 ml) and conc. hydrochloric acid (0.5 ml) are added and the mixture is then extracted with toluene (3 × 10 ml). The combined toluene solution is backwashed with water. The aqueous phase containing a brown oil is rendered alkaline with conc. NH₄ OH and extracted with toluene (3 × 15 ml). The combined toluene solution is washed with water, dried (Na₂ SO₄), treated with charcoal and evaporated under reduced pressure to yield the title compound, identical to the product of the same name described in Example 732.

EXAMPLE 915 1-[2-(Dimethylamino)ethyl]-9-ethyl-1-methyl-1.3.4.9-tetrahydrothiopyrano[3,4-b]indole [1; R¹ = CH₃, R², R³, R⁴, R⁵, and R⁶ = H, R⁷ = C₂ H₅, X = S and Y = CH₂ CH₂ N(CH₃)₂ ]

To a stirred solution of p-toluenesulfonic acid monohydrate (57.0 g) in toluene (400 ml) at 80° C. under nitrogen, the aminoketone, 4-(dimethylamino)-2-butanone (13.8 g), is added. Thereafter, the starting material of formula II, sodium 1-ethylindole-3-ethyl thiosulfate (30.7 g), prepared from 1-ethylindole-3-ethanol according to the procedure of Suvorov and Buyanov, cited above, is added portionwise over a period of 5 minutes. The mixture is maintained at 80° C. for 11/4 hr. with stirring then cooled and diluted with 20% sodium hydroxide (66 ml) followed by water (100 ml) and extracted with toluene. The toluene extract is washed with 20% sulfuric acid (5 × 30 ml) and with water (5 × 30 ml). The combined aqueous phases plus solid precipitating therefrom are rendered alkaline with 20% sodium hydroxide and then extracted with toluene (4 × 50 ml). The combined toluene solution is washed with water, dried (Na₂ SO₄), and evaporated. The residue is recrystallized from ether-hexane to give the title compound, identical to the product of Example 911. The corresponding hydrochloric acid addition salt of the title compound has m.p. 225°-227° C. after recrystallization from isopropanol.

In the same manner but using an equivalent amount of potassium 1-ethylindole-3-ethyl thiosulfate the title compound is also obtained.

By following the procedure of Examples 912, 913, 914 or 915 and using an appropriate starting material of formula II together with the appropriate aminoketone, then other compounds of formula I, for example, those described in Examples 309 - 487 and 675 - 775, are obtained.

EXAMPLE 916 4'-Chloro-2-{methyl[2-(1,3,4,9-tetrahydro-1,9-dimethylpyrano[3,4-b]indole-1-yl)ethyl]amino}-acetophenone[I, R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X=O and Y=CH₂ CH₂ N(CH₃)(p-chlorophenacyl)]

1,9-Dimethyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrobromide (2.0 g), described in Example 675, and 2-bromo-4'-chloro-acetophonone (1.37 g) are dissolved in benzene (10 ml). A solution of sodium hydrogen carbonate (1.2 g) and sodium sulfite (0.06 g) in water (5 ml) are added. The reaction mixture is stirred at room temperature for 3 hr. The aqueous phase is separated and discarded. The organic phase is washed with 0.5 ml or 2N HCl, with water and dried (Na₂ SO₄). After filtration, 2.6 ml of a 2.3 M solution of hydrogen chloride in ether is added. The resulting gummy material is crystallized from methanol and ether to afford the hydrochloric acid addition salt of the title compound, mp. 199° - 205° C (dec.).

Conversion of the latter salt to its free base is achieved washing a chloroform solution of the salt with 5% NaOH solution. Subsequent concentration of the chloroform gives the title compound as the free base, nmr (CDCl₃)δ 1.6(s,3H), 2.3 (s,3H), 3.65 (s,2H) 3.7 (s,3H).

By replacing 1,9-dimethyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole hydrobromide with 9-ethyl-1-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole hydrochloride, described in Example 917, 4'-chloro-2-{[2-(9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1yl)ethyl]methylamino}acetophenone, nmr (CDCl₃) δ 1.40 (t, J = 7.5 Hz, 3H), 1.80 (s, 3H), 2.35 (s, 3H) is obtained; the hydrochloride addition salt of the latter compound has m.p. 175° - 177° C.

EXAMPLE 917 9-Ethyl-1-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano [3,4-b]indole (I; R¹ =CH₃, R², R³, R⁴, R⁵ and R⁶ =H, R⁷ = C₂ H₅, X=S and Y=CH₂ CH₂ NHCH₃)

A mixture of sodium 2-[(1-ethyl-indol-3-yl)ethyl]thiosulfate (12 g.) 4-(formylamino)-2-butanone (6 g), described by H. Bredereck, et al., Chem. Ber., 2423 (1960), toluene (30 ml) and boron trifluoride-etherate (20 ml) is heated at 80° for 4 hr. After cooling, 150 ml of chloroform and 100 ml of saturated sodium bicarbonate are added. The resultant mixture is stirred until the precipitated solids dissolve. The organic phase is separated, washed with water, and concentrated. The residue is purified by chromatography on silica gel, using chloroform and chloroform-methanol (100 : 3) as elements. Combination of major fractions gives the N-formyl derivative, 9-ethyl-1-methyl-1-[2-(formylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano [3,4-b]indole, γ_(max) ^(CHCl).sbsb.3 3410, 1680 cm.sup.⁻¹, nmr (CDCl₃) δ1.38 (t, J=7, 3H), 1.82 (s, 3H), 2.20 (m, 2H), 3.00 (m,6H), 4.31 (q, J=7, 2H), 6.00 (broad), 1H), 7.22 (m, 4H), 7.98 (d, J =2, 1H).

The latter compound (3 g) in 40 ml of dry ether is added to a stirred suspension of lithium aluminium hydride (0.7 g) in 40 ml of the same solvent. The reaction mixture is heated at reflux for 3 hr., decomposed with 4 ml of 30% aqueous solution of sodium-potassium tartrate, and filtered. The filter cake is washed with tetrahydrofuran and the filtrate dried (MgSO₄). Usual work-up afforded the title compound as an oil, nmr (DMSO-d₆) 1.32 (+, J=7, 3H), 1.78 (s, 3H), 7.2 (m,3H).

The hydrochloric acid addition salt of the title compound has mp 259°-261° C after recrystallization from isopropanol-methanol (9 : 1).

This example is a specific embodiment of preparation and conversion of intermediates of formula VII (2=AlK NR⁸ COR²¹), see also Example 782.

EXAMPLE 918 9-Ethyl-1-methyl-1-(2-aminoethyl)-1,3,4,9-tetrahydro-thiopyrano[3,4-b]-indole (I; R¹ =CH₃, R², R³, R⁴, R⁵ and R⁶ =H, R⁷ =C₂ H₅, X=S and Y=CH₂ CH₂ NH₂) ,J=

The N-formyl compound described in Example 917 is hydrolyzed by boiling the compound (1.0 g) in 10 ml of conc. HCl in 10 ml of methanol for 24 hr. The reaction mixture is concentrated under reduced pressure. The aqueous residue is washed with ether, and then rendered basic with 10% NaOH. Extraction with ether affords 9-ethyl--methyl-1-(2-aminoethyl)1,3,4,9-tetrahydrothiopyrano [3,4-b]indole. nmr (CDCl₃) δ 1.40 (+J=7, 3H), 1.82 (s,3H), 1.90 (s, exchangeable, 2H), 4.31 (q,J=7, 2H). Basic hydrolysis (10% NaOH in methanol) of the above N-formyl compound gave product identical with the preceeding product.

The hydrochloric acid addition salt of the latter compound has mp. 257°-258° C after recrystallization from isopropanol ether.

In the same manner as described in the preceding Examples 4 to 784 inclusive and 910 to 918 but replacing the starting material of formula II with the corresponding starting material of formula IIa, the pyrano[4,3-b]indole and thiopyrano [4,3-b]indole derivatives of formula Ia, corresponding to the pyrano [3,4-b]indole and thiopyrano [3,4-b]indole derivatives of formula I, described in these preceding examples, are obtained. This latter aspect of this invention is illustrated further in the following Examples 919 to 921.

EXAMPLE 919 1,5-Dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-acetic acid (Vlla; R¹ and R⁷ =CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X=O and Z=CH₂ COOH)

The compound of formula VI, ethyl acetoacetate (6.5 g), is added to a stirred suspension of aluminium chloride (2.0 g) in anhydrous toluene (60 ml) at 60°. The mixture is stirred until solution is complete residue 10 min.). 2-(1-Methylindole)ethanol (IIa, R², R³, R⁴, R⁵ and R⁶ = CH₃ and X¹ =OH, 8.7 g) in toluene (60 ml) is added dropwise during 40 min. The mixture is stirred for 1 hr at 60° and then cooled to 10° C and treated with water (60 ml). The toluene layer is washed with water, dried and evaporated to dryness. The residue is crystallized from ethanol to give the pure ethyl ester of the title compound, m.p. 136°-138° C.

The ester is hydrolyzed with aqueous ethanol-sodium hydroxide to give the crude acid which crystallized from toluene to give the pure title product, m.p. 181°-112° C.

1-Methylindole-2-ethanyl[nmr(CDCl₃) δ 2.63, 288, 3.55, and 6.12] used in this example is prepared by the method of Julia et al., cited above.

By following the procedure of this example and using the appropriate starting material of formula IIa, together with the appropriate compound of formula VI, other intermediates of formula VIIa are obtained.

EXAMPLE 920 1-[2-(Dimethylamino)ethyl]-1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole [Ia, R¹ and R⁷ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, X = O and Y = CH₂ CH₂ N(CH₃)₂ ]

A solution of 1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-acetic acid ethyl ester (17.0 g), described in Example 916, in tetrahydrofuran (200 ml) is added dropwise to a suspension of lithium aluminium hydride (5.0 g) in tetrahydrofuran (150 ml). The mixture is heated at reflux for 2.5 hr. and then cooled and treated with a mixture of water-tetrahydrofuran (30 ml - 150 ml). The mixture is filtered through celite and the filtrate is evaporated. The residue is purified by chromatography on silica gel. Elution with chloroform gives 1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-ethanol.

A solution of the latter compound (6.5 g) in 75 ml of pyridine, cooled to 0° C, is treated with 10.0 g of p-toluenesulfonyl chloride. The resulting solution is kept at 3° C overnight; thereafter, it is poured into ice water. The mixture is extracted with ether. The extract is washed with water, dried and evaporated at low temperature to give the corresponding tosylate. This material is dissolved in dimethylformamide (DMF, 80 ml) and dimethylamine (16 ml) is added. The mixture is heated under reflux for 1.5 hr. The DMF is evaporated and the residue is dissolved in chloroform. The chloroform solution is washed with water and then evaporated to give the title compound, nmr (CDCl₃) δ 1.62, 2.15 and 4.12, is obtained; the corresponding oxalic acid addition salt thereof having m.p. 139°- 140° C., after crystallization from isopropanol.

By following the same procedure but replacing dimethylamine with an equivalent amount of diethylamine, 1-[2-(diethylaminoethyl]-1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole, nmr (CDCl₃) δ 1.63, 3.65 and 4.05, is obtained; the oxalic acid addition salt thereof having m.p. 122°- 124° C., after crystallization from isopropanol.

By following the procedure of this example and using the appropriate ester of formula VIIa (Z = COOR¹⁹ and Alk¹ --COOR¹⁹), together with the appropriate amine of formula HNR⁸ R⁹ in which R⁸ and R⁹ are as defined in the first instance then other compounds of formula Ia are obtained.

EXAMPLE 921 5-Ethyl-1-methyl-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydrothiopyrano[4,3-b]indole (Ia, R¹ = CH₃, R², R³, R⁴, R⁵ and R⁶ = H, R⁷ = C₂ H₅, X = S and Y = CH₂ CH₂ N(CH₃)₂ ]

A mixture of sodium 2-[(1-ethyl-indol-2-yl)ethyl]thiosulfate (6 g), derived from 1-ethylindole-2-ethanol having nmr (CDCl₃) δ 1.26, 1.99, 2.91, 3.86, 4.08, 6.27, 4-dimethylamio-2-butanone (3 g), toluene (10 ml) and boron trifluoride etherate (10 ml) is heated at 80° for 4 hr. After cooling the reaction mixture is processed in the same manner as described for the work-up of the N-formyl derivative in Example 919 to afford the title compound, nmr CDCl₃) δ 1.3 (t, J = 7, 3H), 1.7 (s, 3H), 2.15 (s, 6H), 4.3 (O, J = 7, 2H).

EXAMPLE 922 (+)- or (-)-1-[2-(Dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole

Racemic 1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, described in Example 915, is separated into its enatiomers by using either (+)- or (-)-mandelic acid. When the racemate is treated with (-)-mandelic acid a mixture of diastereomeric salts is obtained. Upon trituration of the mixture with water, the water-insoluble (-)-mandelate,[α]_(D).sup. 25 = 137° (MeOH), m.p. 110°- 113° C, separates from the water-soluble (+)-madelate, [α]_(D).sup. 25 = + 36.2° C (MeOH). Subsequent decomposition with dilute sodium hydroxide yields the corresponding (+) or (-) free bases, i.e. the title compounds. The (+) base has [α]_(D) ²⁵ = + 43.1° (MeOH) and the (-) base has [α]_(D).sup. 25 = - 44.5° (MeOH). Corresponding hydrochloric acid addition salts have m.p. 224°- 226° C, [α]_(D) ²⁵ = + 10.1° (MeOH) and m.p. 222°- 224° C, [α]_(D) ²⁵ = - 11.1° (MeOH), respectively. 

We claim:
 1. A compound selected from those of the formulae 1 and 1a ##STR104##in which R¹ is lower alkyl or lower cycloalkyl; R², R³, R⁴ and R⁵ are the same or different selected from the group consisting of hydrogen and lower alkyl; R⁶ is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, nitro or halo; R⁷ is hydrogen, lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk-NR⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl, and R⁸ and R⁹ are either the same or different selected from the group consisting of hydrogen and lower alkyl, or R⁸ is lower alkyl and R⁹ is p-chlorophenacyl, or R⁸ and R⁹ together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, 4-(lower alkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl]-1-piperazinyl; X is thio; and Y is lower alkyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of fromula --Alk--NR⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are as defined herein; with the proviso that at least one of R⁷ and Y is --Alk-NR⁸ R⁹ and that in the compounds of formula 1a, Y is -Alk NR⁸ R⁹ as defined herein; or a corresponding acid addition salt thereof with a pharmaceutically acceptable acid.
 2. 1-[2-(Dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 1. 3. 1-[2-(Dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 1. 4. 1,9-Dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 1. 5. 1-[2-(Dimethylamino)ethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 1. 6. 9-Ethyl-1-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 1. 7. 9-Ethyl-1-methyl-1-(2-aminoethyl)-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 1. 8. 5-Ethyl-1-methyl-1-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 1. 9. (+)- or (-)-1-[2-(Dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 3. 10. 9-Allyl-1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, as claimed in claim
 1. 11. A method of relieving the symptoms of depression in warm blooded animals which comprises: administering to said mammal an effective dose of from about 0.1 milligram to about 50 milligrams per kilogram of mammal weight per day of a compound selected from those of the formulae 1 and 1a ##STR105##in which R¹ is lower alkyl or lower cycloalkyl; R², R³, R⁴ and R⁵ are the same or different selected from the group consisting of hydrogen and lower alkyl; R⁶ is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, nitro or halo; R⁷ is hydrogen, lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula -Alk-NR⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵, and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are either the same or different selected from the group consisting of hydrogen and lower alkyl, or R⁸ is lower alkyl and R⁹ is p-chlorophenacyl, or R⁸ and R⁹ together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, 4-(lower alkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl]-1-piperazinyl; X is thio; and Y is lower alkyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk--NR⁸ R⁹ is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are as defined herein; with the proviso that at least one of R⁷ and Y is --Alk--NR⁸ R⁹ and that in the compounds of formula 1a, Y is --Alk NR⁸ R⁹ as defined herein; and the corresponding acid addition salt with a pharmaceutically acceptable acid.
 12. The method of claim 11 in which the compound of formula 1 is 1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or a pharmaceutically acceptable acid addition salt thereof.
 13. The method of claim 11 in which the compound of formula 1 is 1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or a pharmaceutically acceptable acid addition salt thereof.
 14. The method of claim 11 in which the compound of formula 1 is 1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or a pharmaceutically acceptable acid addition salt thereof.
 15. The method of claim 11 in which the compound of formula 1 is 1-[2-(dimethylamino)ethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or a pharmaceutically acceptable acid addition salt thereof.
 16. The method of claim 11 in which the compound of formula 1 is 9-ethyl-1-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or a pharmaceutically acceptable acid addition salt thereof.
 17. The method of claim 11 in which the compound of formula 1 is (+)-or (-)-1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or a pharmaceutically acceptable acid addition salt thereof.
 18. The method of claim 11 in which the compound of formula 1 is 9-allyl-1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or a pharmaceutically acceptable acid addition salt thereof.
 19. A pharmaceutical composition, which comprises: a compound selected from those of the formulae 1 and 1a ##STR106## in which R¹ is lower alkyl or lower cycloalkyl; R². R³, R⁴ and R⁵ are the same or different selected from the group consisting of hydrogen and lower alkyl; R⁶ is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, nitro or halo; R⁷ is hydrogen, lower alkyl, lower alkenyl, propargyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk--NR⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl, and R⁸ and R⁹ are either the same or different selected from the group consisting of hydrogen and lower alkyl, or R⁸ is lower alkyl and R⁹ is p-chlorophenacyl, or R⁸ and R⁹ together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, 4-(lower alkyl)-1-piperazinyl and 4-[hydroxy(lower)alkyl]-1-piperazinyl; X is thio; and Y is lower alkyl, phenyl(lower)alkyl or an amino(lower)alkyl radical of formula --Alk--NR⁸ R⁹ wherein Alk is an alkylene selected from the group consisting of CR¹⁰ R¹¹, CR¹⁰ R¹¹ CR¹² R¹³, CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ and CR¹⁰ R¹¹ CR¹² R¹³ CR¹⁴ R¹⁵ CR¹⁶ R¹⁷ wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen or lower alkyl and R⁸ and R⁹ are as defined herein; with the proviso that at least one of R⁷ and Y is -Alk-NR⁸ R⁹ and that in the compounds of formula 1a, Y is --Alk NR⁸ R⁹ as defined herein; and the corresponding acid addition salt with a pharmaceutically acceptable acid; and a pharmaceutically acceptable carrier.
 20. The composition of claim 19 in which the compound of formula 1 is 1-[2-(dimethylamino)ethyl]-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or the oxalic acid addition salt thereof.
 21. The composition of claim 19 in which the compound of formula 1 is 1,9-dimethyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or the hydrochloric acid addition salt thereof.
 22. The composition of claim 19 in which the compound of formula 1 is 1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or the hydrochloric acid addition salt thereof.
 23. The composition of claim 19 in which the compound of formula 1 is 1-[2-(dimethylamino)ethyl]-1-methyl-9-propyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or the hydrochloric acid addition salt thereof.
 24. The composition of claim 19 in which the compound of formula 1 is 9-ethyl-1-methyl-1-[2-(methylamino)ethyl]-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or the hydrochloric acid addition salt thereof.
 25. The composition of claim 22 in which the compound of formula 1 is (+)- or(-)-1-[2-(dimethylamino)ethyl]-9-ethyl-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or the hydrochloric acid addition salt thereof.
 26. The composition of claim 19 in which the compound of formula 1 is 9-allyl-1-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydro-1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole, or the hydrochloric acid addition salt thereof. 